Methods for Treating GI Tract Disorders

ABSTRACT

Provided herein are methods, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.

CROSS-REFERENCE

This application filed under 35 U.S.C. 111(a) is a continuation ofInternational Patent Application No. PCT/US2013/076733, filed Dec. 19,2013, which claims benefit of U.S. Provisional Patent Application No.61/745,734, filed Dec. 24, 2012, each of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The enteric nervous system (ENS) comprises about one hundred millionneurons embedded in the lining of the gastrointestinal system. The ENSinnervates the gastrointestinal system, including the esophagus, thestomach (e.g., gastric area), and the intestines. Motor neurons of theENS control stomach muscle contractility, peristalsis, and churning ofintestinal contents. It has been estimated that about 50% of the body'sdopamine is found in the ENS.

Gastrointestinal (GI) tract disorders affect many people. Irritablebowel syndrome (IBS), a disorder in which the intestine functionsabnormally due to dysfunction of the muscles or nerves of the GI tract,affects 10 to 15% of the adult population. Symptoms of IBS includeconstipation, diarrhea, and abdominal pain. Functional dyspepsia(dyspepsia caused by a dysfunction of the muscles or nerves associatedwith the upper GI tract) affects 10 to 20% of the adult population.Gastroparesis, a disorder causing inadequate grinding of food by thestomach and delayed gastric emptying, affects up to 10% of the generalpopulation. Gastroesophageal reflux disorder (GERD), a chronic digestivedisease that occurs when stomach acid and/or bile backs up into theesophagus, has been estimated to affect up to 35% of infants in thefirst few months of life.

In addition, gastrointestinal disorders can be associated with a numberof other diseases. For example, some of the earliest symptoms ofParkinson's disease, a disorder characterized by neurodegeneration ofdopamine neurons, include, e.g., constipation and other gastrointestinalsymptoms, likely due to degeneration or dysfunction of ENS dopamineneurons. For other example, diabetes is one of the most common causes ofgastroparesis, as chronic high blood sugar can damage the vagus nervewhich modulates the enteric nervous system. Multiple sclerosis isanother disease that is associated with ENS disorders such as, e.g.,gastroparesis. Migraine headaches are commonly associated with gastricstasis. Chemotherapy-induced nausea and/or vomiting have been estimatedto affect 85% of cancer patients undergoing chemotherapy and can resultin discontinuation of treatment. If the chemotherapy-induced nauseaand/or vomiting are not properly managed, it can cause dehydration andpoor quality of life and may result in discontinuation of chemotherapy.

ENS dysfunction has been implicated in several of the disordersdescribed above. For example, impaired or dysfunctional ENS neuronalsignaling has been strongly implicated as a causative factor forgastroparesis.

There are currently no adequate treatments for these disorders. Forexample, IBS treatments lubiprostone and linaclotide are used to mimicinfectious diarrhea in order to treat constipation; however, theseagents do not correct the underlying ENS dysfunction and are marginallyeffective. The dopamine D2 receptor antagonists domperidone andmetoclopramide have been previously indicated for the treatment ofnausea and vomiting, however, their use is discouraged due tosignificant safety issues. Two significant safety concerns relate to (1)unwanted cardiac side effects caused by, e.g., interaction of the agentswith ion channels involved in cardiac action potentials, and (2)unwanted motor dysfunction caused by the actions of the dopamineantagonists which cross the blood brain barrier into the brain. Forexample, it has been established that many dopamine receptor antagonistsinhibit hERG channels (a type of potassium channel) to causedrug-induced long QT syndrome, a heart condition characterized byabnormal cardiac action potential rhythms. Long QT syndrome can increaserisk of cardiac arrhythmias, which may lead to sudden cardiac death.Indeed, the dopamine D2 antagonist domperidone has been shown to inhibithERG activity and increase risk of long QT syndrome, and increase riskof sudden cardiac death. This has resulted in an FDA ban on the use ofdomperidone in the United States and an initiated review of the safetyof domperidone use by the European Medicines Agency. Metoclopramidecannot be taken for more than 12 weeks and has a black box warning forCNS-related side effects such as tardive dyskinesia, adifficult-to-treat and often incurable disorder characterized byinvoluntary, repetitive body movements.

SUMMARY OF THE INVENTION

Aspects of the present invention relate to methods of treatingdisorders, e.g., functional and motility disorders of thegastrointestinal (GI) tract. Such methods may comprise, e.g., modulatingthe enteric nervous system (ENS). For example, the present inventionprovides for a method of treating functional and motility disorders ofthe GI tract by administrating an effective amount of aperipherally-restricted dopamine receptor D2 antagonist that does nothave adverse cardiac effects on an individual and modulating the entericnervous system (ENS).

The present invention also provides for a method of treatinggastroparesis by administering an effective amount of a composition ofmetopimazine, metopimazine acid, or a prodrug thereof, modulating theENS, and treating gastroparesis.

The present invention also provides for a method of treating vomitingand nausea associated with a GI tract disorder, by administering aneffective amount of a peripherally-restricted dopamine receptor D2antagonist that does not have adverse cardiac effects on an individual,and modulating the ENS.

The present invention provides for a method of improving gastricemptying, by administering an effective amount of aperipherally-restricted dopamine receptor D2 antagonist that does nothave adverse cardiac effects on an individual, and modulating the ENS.

The present invention further provides for a method of improving gastricemptying, by administering an effective amount of carbidopa, andmodulating the ENS.

The present invention provides a method of treating functional andmotility disorders of the GI tract, including the steps of:administrating an effective amount of a compound which is aperipherally-restricted dopamine receptor D2 antagonist that does nothave adverse cardiac effects on an individual; and modulating theenteric nervous system (ENS). In some embodiments, the GI tract disorderis chosen from the group consisting of IBS/abdominal pain, functionaldyspepsia, gastroparesis, cyclic vomiting syndrome, chemotherapy-inducednausea and vomiting. The invention also provides a method of treatinggastroparesis, including the steps of: administering an effective amountof a compound chosen from the group consisting of metopimazine,metopimazine acid, and a prodrug thereof; modulating the enteric nervoussystem (ENS); and treating gastroparesis.

The invention also provides a method of treating vomiting and nauseaassociated with a GI tract disorder, including the steps of:administering an effective amount of a peripherally-restricted dopaminereceptor D2 antagonist that does not have adverse cardiac effects on anindividual; and modulating the enteric nervous system (ENS).

The invention also provides a method of improving gastric emptying,including the steps of: administering an effective amount of aperipherally-restricted dopamine receptor D2 antagonist that does nothave adverse cardiac effects on an individual; and modulating theenteric nervous system (ENS).

In any of the foregoing methods, the compound may be chosen from thegroup consisting of metopimazine and metopimazine acid, and prodrugsthereof. In some embodiments, the compound is a prodrug of metopimazineacid chosen from the group consisting of ethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate,[2-(dimethylamino)-2-oxo-ethyl]1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate,2-dimethylaminoethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate,1-(2-methylpropanoyloxyl)ethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate,and2-[[1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carbonyl]amino]propanoicacid. In some embodiments, the composition is administered at 10 mg to60 mg every four hours.

The invention also provides a method of improving gastric emptying,including the steps of: administering an effective amount of carbidopa;and modulating the enteric nervous system (ENS). In some embodiments,the method further includes the step of administering an effectiveamount of the peripherally-restricted dopamine receptor D2 antagonistthat does not have adverse cardiac effects on an individual chosen fromthe group consisting of metopimazine, metopimazine-acid (MPZA), andprodrugs thereof.

The invention also provides a method of treating an enteric nervoussystem disorder in a human subject in need thereof, comprisingadministering to the subject an effective dose of a compound comprisinga phenothiazine group or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof to the subject for over 5 days.

The invention also provides a method of treating an enteric nervoussystem disorder in a subject in need thereof, comprising administeringto the subject an effective dose of a compound comprising aphenothiazine group or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof to the subject for over 7 days.

The invention also provides a method of treating an enteric nervoussystem disorder in a subject in need thereof, comprisingco-administering to the subject an effective dose of compound comprisinga phenothiazine group or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof, and a dopamine decarboxylase inhibitor.

The invention also provides a method of treating an enteric nervoussystem disorder in a subject in need thereof, comprising administeringto the subject an effective dose of a dopamine decarboxylase inhibitor.In some embodiments, the dopamine decarboxylase inhibitor does not crossa blood-brain barrier of the subject. In some embodiments, the dopaminedecarboxylase inhibitor is carbidopa. In some embodiments, the dopaminedecarboxylase inhibitor is selected from the group consisting ofBenserazide, Methyldopa, or α-Difluoromethyl-DOPA (DFMD, DFM-DOPA).

The invention also provides a method of treating an enteric nervoussystem disorder in a human subject in need thereof, comprisingadministering to the subject a compound that is a peripherallyrestricted dopamine D2 receptor antagonist, or a pharmaceuticallyacceptable salt, solvate, metabolite, or prodrug thereof, for over 12weeks, wherein the peripherally restricted dopamine D2 receptorantagonist is not domperidone and is not a compound of Formula (Y):

wherein X is —CH═CH—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—CH₂—, —CH₂—S—,—S—, or —O—, and R is a 5- or 6-membered nitrogen heterocyclic ringoptionally fused to a benzo group. In some embodiments, the peripherallyrestricted dopamine D2 receptor antagonist exhibits minimal hERGinhibition.

In any of the foregoing methods, the compound may comprise the structureof Formula I

wherein, R₁ and R₂ are each independently selected from H, cyano, nitro,azido, halo, —CF₃, unsubstituted C₁-C₄ alkyl, —SR₄, —S(O)R₄, —S(O)₂R₄,—NR₄R₄, —OR₄ and C₁-C₄ alkyl substituted with halo, —OR₄, —SR₄, —S(O)R₄,—S(O)₂R₄, and —OR₄; each R₄ is independently selected from H and C₁-C₄alkyl; L a bond or C₁-C₁₀ alkyl optionally substituted with —OR₄ or—NR₄R₄; and R₃ is H, —NR₄R₄, or C₃-C₇ heterocycloalkyl having 1, 2, or 3heteroatoms selected from N, O, and S in the ring, wherein theheterocycloalkyl group if present is optionally substituted with an arylgroup, R₄, —CO₂H, —CO₂R₄, —C(O)NR₄R₄ and or C₁-C₄ alkyl optionallysubstituted with —OR₄, —NR₄R₄.

In some embodiments, the compound has the structure of the Formula II

wherein: R₁ is H, halo, —CF₃, unsubstituted C₁-C₄ alkyl, —SR₄, —S(O)R₄,—S(O)₂R₄, or —OR₄; each R₄ is independently selected from H and C₁-C₄alkyl; L is a bond or C₁-C₆ alkyl; and R₃ is H, —NR₄R₄, or C₃-C₇heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and Sin the ring, wherein the heterocycloalkyl group if present is optionallysubstituted with, —CO₂H, —CO₂R₄, —C(O)NR₄R₄, and or C₁-C₄ alkyloptionally substituted with —OR₄, —NR₄R₄.

In some embodiments, the compound is a compound of Formula III

In some embodiments, the compound is of Formula IV:

In some embodiments, the compound is of Formula V:

wherein X is O or NH; R₅ is C₁-C₆ linear or branched alkyl, benzyl,CH₂OH, CH₂CH₂OH, or CH₂CH₂SMe; Y and Z are both hydrogen or together canbe a carbonyl oxygen; R₆ is OH, OR₇, or NR₈R₉; and R₇, R₈, and R₉ areindependently C₁-C₄ linear or branched alkyl.

In some embodiments, the compound is of Formula VI:

wherein R₁₀ is C₁-C₄ linear or branched alkyl; and R₁₁ is C₁-C₆ linearor branched alkyl, phenyl, or C₄-C₇ cycloalkyl.

In some embodiments, the compound is of Formula VII:

In some embodiments, the compound is of Formula VIII:

In some embodiments, the compound is of Formula IX:

In some embodiments, the compound is of Formula X:

In some embodiments, the compound is of Formula XI:

In some embodiments of methods described herein, the subject is amammal. In some embodiments, the mammal is a human. In some embodiments,the subject is not an adult. In some embodiments, the enteric nervoussystem disorder is a chronic disorder. In some embodiments, the entericnervous system disorder is selected from the group consisting ofgastroparesis, Irritable Bowel Syndrome, lysosomal storage disorders,intestinal dysmotility, ganglioneuroma, multiple endocrine neoplasiatype 2B (MEN2B), gastrointestinal neuropathy, and intestinal neuronaldysplasia. In some embodiments, the enteric nervous system disorder isgastroparesis. In some embodiments, the disorder has a symptom which isselected from the group consisting of nausea, vomiting, delayed gastricemptying, diarrhea, abdominal pain, gas, bloating, gastroesophagealreflux, reduced appetite, and constipation. In some embodiments, thesymptom is associated with Scleroderma, Parkinson's Disease,gastroesophageal reflux disease, Menetrier's Disease, a vestibulardisorder, chemotherapy, cancer, drug use, and functional dyspepsia.

In any of the foregoing methods, the compound may be administeredorally, parenterally, enterally, intraperitoneally, topically,transdermally, ophthalmically, intranasally, locally, non-orally, viaspray, subcutaneously, intravenously, intratonsillary, intramuscularly,buccally, sublingually, rectally, intra-arterially, by infusion, orintrathecally. In any of the foregoing methods, the compound may beformulated in a pharmaceutical composition comprising a physiologicallyacceptable vehicle. In some embodiments, the pharmaceutical compositionis formulated as a tablet, a capsule, a cream, a lotion, an oil, anointment, a gel, a paste, a powder, a suspension, a syrup, an enema, anemulsion, or a solution, a controlled-release formulation. In someembodiments, the pharmaceutical composition is a syrup, an enema, or atablet. In some embodiments, the tablet is an orally disintegratingtablet. In some embodiments, the method comprises administering morethan 30 mg of the compound a day. In some embodiments, the methodcomprises administering the compound for over 12 weeks. In someembodiments, the method comprises administering the compound four timesper day.

In some embodiments of any of the foregoing methods, the administeringdoes not increase probability that the subject will suffer an adversecardiac side effect. In some embodiments, the administering does notincrease probability that the subject will suffer an adverseextrapyramidal side effect in the subject. In some embodiments, thecompound does not effectively cross a blood brain barrier. For example,in some embodiments, the dopamine decarboxylase inhibitor does not crossa blood brain barrier. In some embodiments, the dopamine decarboxylaseinhibitor is carbidopa.

In some embodiments of any of the foregoing methods, the methodcomprises coadministering an additional therapeutic agent. In someembodiments, the additional therapeutic agent is selected from the groupconsisting of serotonin agonists, serotonin antagonists, selectiveserotonin reuptake inhibitors, anticonvulsants, opioid receptoragonists, bradykinin receptor antagonists, NK receptor antagonists,adrenergic receptor agonists, benzodiazepines, gonadotropin-releasinghormone analogues, calcium channel blockers, and somatostatin analogs.In some embodiments, the coadministering comprises administering theadditional therapeutic agent in a single composition with the compoundand/or dopamine decarboxylase inhibitor. In some embodiments, thecoadministering comprises administering the additional therapeutic agentsequentially with the compound and/or dopamine decarboxylase inhibitor.In some embodiments, the coadministering comprises administering theadditional therapeutic agent simultaneously with the compound and/ordopamine decarboxylase inhibitor.

The invention also provides a kit, comprising: (a) at least one unitdosage of a pharmaceutical composition comprising a compound of FormulaI:

wherein, R₁ and R₂ are each independently selected from H, cyano, nitro,azido, halo, —CF₃, unsubstituted C₁-C₄ alkyl, —SR₄, —S(O)R₄, —S(O)₂R₄,—NR₄R₄, —OR₄ and C₁-C₄ alkyl substituted with halo, —OR₄, —SR₄, —S(O)R₄,—S(O)₂R₄, and —OR₄; each R₄ is independently selected from H and C₁-C₄alkyl; L a bond or C₁-C₁₀ alkyl optionally substituted with —OR₄ or—NR₄R₄; and R₃ is H, —NR₄R₄, or C₃-C₇ heterocycloalkyl having 1, 2, or 3heteroatoms selected from N, O, and S in the ring, wherein theheterocycloalkyl group if present is optionally substituted with an arylgroup, R₄, —CO₂H, —CO₂R₄, —C(O)NR₄R₄ and or C₁-C₄ alkyl optionallysubstituted with —OR₄, —NR₄R₄; and (b) instructions for carrying out anyof the foregoing methods. In some embodiments, the compound has thestructure of the Formula II:

wherein: R₁ is H, halo, —CF₃, unsubstituted C₁-C₄ alkyl, —SR₄, —S(O)R₄,—S(O)₂R₄, or —OR₄; each R₄ is independently selected from H and C₁-C₄alkyl; L is a bond or C₁-C₆ alkyl; and R₃ is H, —NR₄R₄, or C₃-C₇heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and Sin the ring, wherein the heterocycloalkyl group if present is optionallysubstituted with, —CO₂H, —CO₂R₄, —C(O)NR₄R₄, and or C₁-C₄ alkyloptionally substituted with —OR₄, —NR₄R₄.

In some embodiments, the compound is a compound of Formula III:

In some embodiments, the compound is of Formula IV:

In some embodiments, the compound is of Formula V:

wherein X is O or NH; R₅ is C₁-C₆ linear or branched alkyl, benzyl,CH₂OH, CH₂CH₂OH, or CH₂CH₂SMe; Y and Z are both hydrogen or together canbe a carbonyl oxygen; R₆ is OH, OR₇, or NR₈R₉; and R₇, R₈, and R₉ areindependently C₁-C₄ linear or branched alkyl.

In some embodiments, the compound is of Formula VI:

wherein R₁₀ is C₁-C₄ linear or branched alkyl; and R₁₁ is C₁-C₆ linearor branched alkyl, phenyl, or C₄-C₇ cycloalkyl.

In some embodiments, the compound is of Formula VII:

In some embodiments, the compound is of Formula VIII:

In some embodiments, the compound is of Formula IX:

In some embodiments, the compound is of Formula X:

In some embodiments, the compound is of Formula XI:

The invention also provides a kit, comprising: (a) at least one unitdosage of a pharmaceutical composition comprising a dopaminedecarboxylase inhibitor; and (b) instructions for carrying out any ofthe foregoing methods. In some embodiments, the dopamine decarboxylaseinhibitor does not cross a blood-brain barrier of the subject. In someembodiments, the dopamine decarboxylase inhibitor is carbidopa. In someembodiments, the dopamine decarboxylase inhibitor is selected from thegroup consisting of Benserazide, Methyldopa, or α-Difluoromethyl-DOPA(DFMD, DFM-DOPA). In some embodiments, the kit further comprises atleast one dosage form of a composition comprising a compound of any oneof Formulas I-XI described herein.

In some embodiments, the invention provides a use of any of theforegoing compounds in the preparation of a medicament for the treatmentof a disorder, e.g., an enteric nervous system disorder. In someembodiments, the medicament is prepared for administration for over 5days.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts a drawing of the chemical structure of metopimazine; and

FIG. 2 depicts results from a gastric motility assay in canines treatedwith metopimazine, carbidopa, and dopamine.

FIG. 3 depicts results from a gastric emptying assay in rodents treatedwith metopimazine and metoclopramide.

DETAILED DESCRIPTION OF THE INVENTION

General Techniques:

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of immunology, biochemistry,chemistry, molecular biology, microbiology, cell biology, genomics andrecombinant DNA, which are within the skill of the art. See, e.g.,Sambrook, Fritsch and Maniatis, MOLECULAR CLONING: A LABORATORY MANUAL,4th edition (2012); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M.Ausubel, et al. eds., (1987)); the series METHODS IN ENZYMOLOGY(Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M. J. MacPherson,B. D. Hames and G. R. Taylor eds. (1995)), and CULTURE OF ANIMAL CELLS:A MANUAL OF BASIC TECHNIQUE AND SPECIALIZED APPLICATIONS, 6th Edition(R. I. Freshney, ed. (2010), which are hereby incorporated by reference.

As used in the specification and claims, the singular forms “a”, “an”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “a cell” includes a plurality of cells,including mixtures thereof.

DEFINITIONS

The term “agonist,” as used herein, generally refers to a molecule suchas a compound, a drug, an enzyme activator or a hormone modulator thatbinds to a specific receptor and triggers a response in the cell. Anagonist generally mimics the action of an endogenous ligand (such a,e.g., dopamine) that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents a cellular response toa receptor activated by an agonist. Antagonists can include, but are notlimited to, competitive antagonists, non-competitive antagonists,uncompetitive antagonists, partial agonists and inverse agonists.Competitive antagonists can reversibly bind to receptors at the samebinding site (active site) as the endogenous ligand or agonist, withoutnecessarily activating the receptor. Non-competitive antagonists (alsoknown as allosteric antagonists) can bind to a distinctly separatebinding site from the agonist, exerting their action to that receptorvia the other binding site. Non-competitive antagonists generally do notcompete with agonists for binding. Binding of a non-competitiveantagonist to the receptor may result in a decreased affinity of anagonist to that receptor. Alternatively, binding of a non-competitiveantagonist to a receptor may prevent a conformational change in thereceptor required for agonist-mediated receptor activation.Uncompetitive antagonists may require receptor activation by an agonistbefore they can bind to a separate allosteric binding site. Partialagonists can refer to molecules which, at a given receptor, might differin the amplitude of the functional response that they elicit aftermaximal receptor occupancy. Although they are agonists, partial agonistscan act as a competitive antagonist if co-administered with a fullagonist, as it competes with the full agonist for receptor occupancy andproducing a net decrease in the receptor activation observed with thefull agonist alone. An inverse agonist can have effects similar to anantagonist, but causes a distinct set of downstream biologicalresponses. Constitutively active receptors which exhibit intrinsic orbasal activity can have inverse agonists, which not only block theeffects of binding agonists like a classical antagonist, but inhibit thebasal activity of the receptor.

As used herein, a compound that is “peripherally restricted” generallyrefers to a compound that does not substantially cross an intact bloodbrain barrier of a subject. The term also encompasses compounds that maycross an intact blood brain barrier, but upon administration to asubject is rapidly metabolized to a form that does not substantiallycross an intact blood brain barrier of the subject. A compound may beconsidered “peripherally restricted” if, upon administration to asubject, less than 50%, less than 45%, less than 40%, less than 35%,less than 30%, less than 25%, less than 20%, less than 15%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1%, less than0.5%, less than 0.1% of the compound crosses an intact blood brainbarrier of the subject.

As used herein, the terms “treatment” or “treating” are usedinterchangeably herein. These terms refer to an approach for obtainingbeneficial or desired results including but not limited to a therapeuticbenefit and/or a prophylactic benefit. A therapeutic benefit can meaneradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit can be achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder. A prophylactic effect includes delaying oreliminating the appearance of a disease or condition, delaying oreliminating the onset of symptoms of a disease or condition, slowing,halting, or reversing the progression of a disease or condition, or anycombination thereof. For prophylactic benefit, the compositions may beadministered to a subject at risk of developing a particular disease, orto a subject reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “sub-therapeutic amount” of an agent is an amount less than theeffective amount for that agent. When combined with an effective orsub-therapeutic amount of one or more additional agents, thesub-therapeutic amount can produce a result desired by the physician,due to, for example, synergy in the resulting efficacious effects, orreduced adverse effects.

A “synergistically effective” therapeutic amount or “synergisticallyeffective” amount of an agent or therapy is an amount which, whencombined with an effective or sub-therapeutic amount of one or moreadditional agents, produces a greater effect than when either of theagents are used alone. In some embodiments, a synergistically effectivetherapeutic amount of an agent or therapy produces a greater effect whenused in combination than the additive effects of any of the individualagents when used alone. The term “greater effect” encompasses not only areduction in symptoms of the disorder to be treated, but also animproved side effect profile, improved tolerability, improved patientcompliance, improved efficacy, or any other improved clinical outcome.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “determining”, “measuring”, “evaluating”, “assessing,”“assaying,” and “analyzing” are used interchangeably herein to refer toany form of measurement, and include determining if an element ispresent or not. These terms include both quantitative and/or qualitativedeterminations. Assessing may be relative or absolute. “Assessing thepresence of” includes determining the amount of something present, aswell as determining whether it is present or absent.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

The term “prodrug”, as used herein, generally refers to an agent that isconverted into the parent drug in vivo.

The term “alkyl”, as used herein, refers to a hydrocarbon chain that isa straight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁-C₄ alkyl group indicates that the grouphas from 1 to 4 (inclusive) carbon atoms in it. Similarly, C₁-C₁₀ alkylgroup indicates that the group has from 1 to 10 (inclusive) carbon atomsin it. The alkyl may be unsubstituted or substituted with one or moresubstituents.

The term “halo” or “halogen”, as used herein, refers to fluoro, chloro,bromo, or iodo.

The term “cycloalkyl”, as used herein, refers to a carbon cyclicaliphatic ring structure, for example, a 4-7 carbon cyclic structure.The cycloalkyl may be unsubstituted or substituted with one or moresubstituents.

The term “heterocycloalkyl” or “heterocyclic ring” refers to asubstituted or unsubstituted 3-, 4-, 5-, 6- or 7-membered saturated orpartially unsaturated ring containing one, two, or three heteroatoms,independently selected from oxygen, nitrogen and sulfur;Heterocycloalkyl may be unsubstituted or substituted with one or moresubstituents. The heterocycloalkyl may be optionally fused to anothercycloalkyl, heterocycloalkyl, or an aryl. For example, to a benzo group.

“Aromatic” or “aryl” refers to an aromatic radical with six to ten ringatoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,benzyl, phenyl, fluorenyl, and naphthyl). The term includes monocyclicor fused-ring polycyclic groups. An aryl moiety is unsubstituted orsubstituted with one or more substituents.

The term “cyano”, as used herein, refers to a carbon linked to anitrogen by a triple bond, i.e., —C≡N.

The term “nitro”, as used herein, refers to a NO₂ substituent.

The term “azido”, as used herein refers to a N₃ substituent.

Compounds described can contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof.

Overview

Certain phenothiazine compounds can be safely administered to a subjectwithout increasing risk of an adverse cardiac symptom or increasing riskof an adverse motor symptom in the subject. Accordingly, the inventionprovides a method, comprising administering to a subject a compoundcomprising a phenothiazine group or a pharmaceutically acceptable salt,solvate, metabolite, or prodrug thereof to the subject for over 5 days.In some embodiments, the administering effectively treats a disorder inthe subject. The disorder can be, e.g., a gastrointestinal disorder,and/or an ENS disorder. The invention also provides a method of treatingan ENS disorder in a subject in need thereof, comprising administeringto the subject a compound that is a peripherally restricted dopamine D2receptor antagonist, or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof, for over 12 weeks. In some embodiments,the peripherally restricted dopamine D2 receptor antagonist is notdomperidone and is not a compound of Formula (Y):

wherein X is —CH═CH—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—CH₂—, —CH₂—S—,—S—, or —O—, and R is a 5- or 6-membered nitrogen heterocyclic ringoptionally fused to a benzo group.

Some dopamine decarboxylase inhibitors can effectively promote gastricmotility. Accordingly, the invention provides a method of treating anENS disorder in a subject in need thereof, comprising administering tothe subject an effective dose of a dopamine decarboxylase inhibitor. Insome embodiments, the method comprises co-administering to the subjectan effective dose of compound comprising a phenothiazine group or apharmaceutically acceptable salt, solvate, metabolite, or prodrugthereof, and a dopamine decarboxylase inhibitor.

Exemplary Subjects

The compounds can be used for the treatment of a disorder in a subjectin need thereof. The subject may be suffering from, may be diagnosedwith, may be exhibiting a symptom of, or may be suspected of having thedisorder. The disorder can be a gastrointestinal disorder, an entericnervous system disorder, or other disorder. The disorder may becharacterized by a hypomotility of at least a portion of thegastrointestinal tract. For example, the disorder can be characterizedby hypomotility of the stomach and/or intestine. The hypomotility may becaused by aberrant ENS neuronal signaling, for example, by aberrantdopamine signaling activity.

In some embodiments, the enteric nervous system disorder isgastroparesis. The terms “gastroparesis” and “delayed gastric emptying”are used interchangeably herein to refer to a disorder that, e.g., slowsor stops the movement of food from the stomach to the small intestine.Normally, the muscles of the stomach, which are controlled by the vagusnerve, contract to break up food and move it through thegastrointestinal (GI) tract. Gastroparesis can occur, for example, whenthe vagus nerve is damaged by illness or injury, causing the stomachmuscles stop working normally. In subjects with gastroparesis, food canmove slowly from the stomach to the small intestine or may stop movingaltogether. Accordingly, the subject may be suffering from, may bediagnosed with, may be exhibiting a symptom of, or may be suspected ofhaving gastroparesis.

A subject may be suspected of having gastroparesis if the subjectexhibits or has exhibited a symptom of gastroparesis. Symptoms ofgastroparesis can include gastroesophageal reflux (GER), also calledacid reflux or acid regurgitation. Gastroesophageal reflux generallyrefers to a condition in which stomach contents flow back up into theesophagus. Other symptoms associated with gastroparesis include, but arenot limited to, pain and/or burning sensation in the stomach area,abdominal bloating, lack of appetite, anorexia, malnutrition, nausea,and vomiting. A symptom of gastroparesis can be mild or severe, and canoccur frequently or infrequently. A symptom of gastroparesis can vary inseverity over time in the same subject. Accordingly, the subject mayexhibit or has exhibited GER, pain and/or burning sensation in thestomach area, abdominal bloating, lack of appetite, anorexia,malnutrition, nausea, and/or vomiting.

The subject may be diagnosed with gastroparesis. Gastroparesis may bediagnosed by any means known to those of skill in the art or otherwisedescribed herein. Gastroparesis may be diagnosed, e.g., through aphysical exam, medical history, blood tests, tests to rule out blockageor structural problems in the GI tract, gastric emptying assays, andassays of GI contractile activity. Tests may also identify a nutritionaldisorder or underlying disease. Tests that are useful in diagnosinggastroparesis include, but are not limited to, upper gastrointestinal(GI) endoscopy, upper GI series, ultrasound tests, gastric emptyingscintigraphy, gastric emptying breath test, antral manometry,electrogastrography, and/or electrogastroenterography.

Upper GI endoscopy can be used to rule out other conditions that couldresult in delayed gastric emptying (such as, e.g., a physicalobstruction). Upper GI endoscopy typically involves use of an endoscope(e.g., a small, flexible tube with a light) to visualize the upper GItract, including, e.g., the esophagus, stomach, and duodenum (the firstpart of the small intestine). The endoscope is generally used to imagethe stomach and/or duodenum. A small camera mounted on the endoscope cantransmit a video image to a monitor, allowing close examination of theintestinal lining. Upper GI endoscopy may show physical blockage of theupper GI tract, for example, a large bezoar (e.g., solid collections offood, mucus, vegetable fiber, hair, or other material). In someembodiments, the subject is diagnosed with gastroparesis if the subjectexhibits a symptom of gastroparesis and upper GI endoscopy does notreveal a physical blockage causing the delayed gastric emptying.

An upper GI series may be performed to look at the small intestine. Thetest may be performed at a hospital or outpatient center by an x-raytechnician, and the images may be interpreted by a radiologist. Duringthe procedure, the subject may stand or sit in front of an x-ray machineand drink barium, a chalky liquid. Barium may coat the small intestine,making signs of gastroparesis show up more clearly on x rays.Gastroparesis may be indicated in cases wherein the x-ray shows food inthe stomach after fasting. In some embodiments, the subject is diagnosedwith gastroparesis if an upper GI series reveals food in the stomachafter fasting.

Ultrasound can be useful in ruling out other syndromes which may sharesymptoms in common with gastroparesis. Such other syndromes includegallbladder disease and pancreatitis. Ultrasound generally uses adevice, called a transducer, that bounces safe, painless sound waves offorgans to create an image of their structure. The procedure can beperformed in a health care provider's office, outpatient center, orhospital by a specially trained technician. Ultrasound images may beinterpreted by a radiologist. The subject may be diagnosed withgastroparesis if the subject exhibits a symptom of gastroparesis andother syndromes such as, e.g., gallbladder disease, pancreatitis, areruled out by, for example, ultrasound.

Gastric emptying scintigraphy can be used to diagnose gastroparesis in asubject. Gastric emptying scintigraphy can involve ingestion of a blandmeal—such as eggs or an egg substitute—that contains a small amount ofradioactive material. The radioactive material may be 99-M Technetium(TC) sulfur colloid or other radioactive ligand. The test may beperformed in a radiology center or hospital. An external camera may beused to detect and/or measure radioactivity in the abdominal region.Radioactivity may be measured at timed intervals, e.g., at 1, 2, 3, and4 hours after the meal. Gastroparesis may be positively identified insubjects exhibiting more than 10 percent of the meal within the stomachat 4 hours. Other measures of gastric emptying include, but are notlimited to, the time at which 50% of the meal has been emptied out ofthe stomach. See, e.g., Thomforde, G. M. et al., Evaluation of aninexpensive screening scintigraphic test of gastric emptying, 36 J.Nucl. Med. 93 (1995), hereby incorporated by reference. In someembodiments, the subject is diagnosed with gastroparesis via gastricemptying scintigraphy.

A breath test useful for assessing gastric emptying can utilizeradioactively labeled food (e.g., labeled with C¹³-octanoic acid). C¹³from the food may be absorbed when it reaches the small bowel. Theabsorbed C¹³ can then be rapidly metabolized in the liver to produce¹³CO₂. The produced ¹³CO₂ may then be detected in the breath of thesubject. The subject's breath may be collected and sampled at definedintervals. The samples may be analyzed for ¹³CO₂ by any means known inthe art. The rate of appearance of ¹³CO₂ in the breath can be used toindicate the rate of gastric emptying. An exemplary method of performinga C¹³-octanoic acid breath test is described in Ghoos, Y. S., et al.,104 Gastroenterology 1640-1647 (1993), hereby incorporated by reference.In some embodiments, the subject is diagnosed with gastroparesis via abreath test.

Manometry generally refers to the assessment of pressure changes in alumen. Antral manometry, which can also be referred to as antro-duodenalmanometry, generally refers to techniques for the evaluation ofcontractile activity in the distal stomach and duodenum. Intraluminalpressure of the stomach and/or duodenum can be measured through pressuresensors which are introduced into the lumen via a catheter. Measurementsmay be recorded over time in order to assess intraluminal pressurechanges. Recordings may last for any amount of time. Intraluminalpressure changes can be used to indicate contractile patterns in thestomach and/or duodenum. Intraluminal pressure changes may be measuredin a fasting state and/or after ingestion of a meal (post-prandially).Post-prandial contractile hypomotility can be indicative ofgastroparesis in a subject. Accordingly, a subject may exhibitpost-prandial gastric hypomotility, as determined by manometry.

Electrogastrography generally refers to techniques and methods forrecording electrical activity of the stomach. Likewise,electrogastroenterography refers to techniques and methods for recordingelectrical activity of the stomach and small intestine. Such electricalactivity can be recorded from the gastrointestinal mucosa, serosa, orthe outer skin surface (cutaneously). Gastrointestinal mucosa can referto the mucous membrane layer of the GI tract. Gastrointestinal serosacan comprise a thin layer of cells which secrete serous fluid, and athin epithelial layer. Recordings can be made during a fasting state,and after ingestion of a meal (usually 60 minutes). Deviations from thenormal frequency of electrical activity can include bradygastria and/ortachygastria. Control subjects typically exhibit an increase inelectrical activity after a meal, indicative of increased GI motility.Subjects with aberrant GI motility can exhibit abnormal rhythms inactivity and/or impairments in the postprandial increase. A normalfrequency of GI electrical activity can be, e.g., 3 cycles per minute.Bradygastria, which can be characterized as a frequency of GI electricalactivity that is decreased from normal, e.g., that is less than 2 cyclesper minute for at least one minute, can be indicative of gastroparesis.In some embodiments, a subject may exhibit bradygastria.Electrogastrography (EGG) which measures electrical activity withcutaneous electrodes similar to those used in electrocardiograms canalso be used to diagnose gastroparesis. (Stern, R. N. et al. EGG: Commonissues in validation and methodology, 24 Psychophysiology 55-64 (1987)),hereby incorporated by reference. Accordingly, a subject may bediagnosed with gastroparesis as determined by electrogastrography.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having gastroesophagealreflux disease (GERD). GERD can be a chronic condition resulting ingastroesophageal reflux. Symptoms of GERD include, e.g., heartburn, dry,chronic cough, wheezing, athsma, recurrent pneumonia, nausea, vomiting,sore throat, difficulty swallowing, pain in the chest or upper abdomen,dental erosion, bad breath, spitting up. GERD may be diagnosed with theaid of tests. Tests that are useful in the diagnosis of GERD include,e.g., upper GI series, described herein, upper endoscopy, esophageal pHmonitoring, and esophageal manometry.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having enteric nervoussystem disorder which is associated with a vestibular disorder of theear. The vestibular disorder of the ear can be Menetrier's disease.Ménétrier disease can be characterized by enlargement of ridges (alsoreferred to herein as rugae) along the inside of the stomach wall,forming giant folds in the lining of the stomach. Ménétrier disease mayalso cause a decrease in stomach acid resulting from a reduction inacid-producing parietal cells. Symptoms of Ménétrier disease include, byway of example only, severe stomach pain, nausea, frequent vomiting, andthe like.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having cyclical vomitingsyndrome (CVS). Cyclical vomiting syndrome can be characterized byepisodes or cycles of severe nausea and vomiting that alternate withsymptom-free intervals. Such episodes can last for hours, or even days.Episodes can start at the same time of day, can last the same length oftime, and can occur with the same symptoms and level of intensity.Episodes can be so severe that a person has to stay in bed for days,unable to go to school or work. Other symptoms of cyclical vomitingsyndrome include, e.g., abdominal pain, diarrhea, fever, dizziness, andsensitivity to light during vomiting episodes. Continued vomiting maycause severe dehydration that can be life threatening. Symptoms ofdehydration include thirst, decreased. Cyclical vomiting syndrome may bediagnosed in a subject who has experienced the following symptoms for atleast 3 months: vomiting episodes that start with severevomiting—several times per hour—and last less than 1 week, three or moreseparate episodes of vomiting in the past year, and absence of nausea orvomiting between episodes.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having Irritable BowelSyndrome (IBS). IBS generally refers to a syndrome in which subjectsexperience recurrent or chronic gastrointestinal symptoms. Symptoms ofIBS can include, e.g., abdominal pain, abdominal discomfort,constipation, diarrhea, mucus in the stool, abdominal bloating, or acombination of any of the above. IBS may be diagnosed when a person hashad abdominal pain or discomfort at least three times a month for thelast 3 months without other disease or injury that could explain thepain. The pain or discomfort of IBS may occur with a change in stoolfrequency or consistency or be relieved by a bowel movement. IBS can beclassified into four subtypes based on a subject's usual stoolconsistency. The four subtypes of IBS are: IBS with constipation(IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), and unsubtypedIBS (IBS-U). A subject with IBS-C may have hard or lumpy stools at least25 percent of the time, may have loose or watery stools less than 25percent of the time, or a combination of the two. A subject with IBS-Dmay have loose or watery stools at least 25 percent of the time, hard orlumpy stools less than 25 percent of the time, or a combination of thetwo. A subject with IBS-M may have hard or lumpy stools at least 25percent of the time and loose or watery stools at least 25 percent ofthe time. A subject with IBS-U may have hard or lumpy stools less than25 percent of the time, loose or watery stools less than 25 percent ofthe time, or a combination of the two. Constipation associated with IBSmay be due to slow or delayed gastric motility. In some embodiments, thesubject with IBS has experienced constipation. IBS can be diagnosed in asubject by any means known in the art or otherwise described herein. Forinstance, IBS may be diagnosed by a health care provider. The healthcare provider may conduct a physical exam and may take a medical historyof the subject. IBS may be diagnosed if a subject has exhibited one ormore symptoms of IBS for at least 3, 4, 5, or 6 months, with one or moresymptoms occurring at least three times a month for the previous 3months. Additional tests that may be useful in the diagnosis of IBSinclude, but are not limited to: a stool test, lower GI series, flexiblesigmoidoscopy, or colonoscopy.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having functionaldyspepsia (e.g., impaired digestion). Symptoms of dyspepsia include,e.g., chronic or recurrent pain in the upper abdomen, upper abdominalfullness, bloating, belching, nausea, and heartburn. Functionaldyspepsia (e.g., nonulcer dyspepsia) generally refers to dyspepsiawithout evidence of an organic disease that is likely to explain thesymptoms of dyspepsia. An example of functional dyspepsia is dyspepsiain the absence of an ulcer. Functional dyspepsia is estimated to affectabout 15% of the general population in western countries. Otherexemplary ENS disorders include, e.g., intestinal dysmotility,ganglioneruoma, multiple endocrine neoplasia type 2B (MEN2B),gastrointestinal neuropathy, and intestinal neuronal dysplasia.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having an entericnervous system disorder caused by another underlying disease. Forexample, the enteric nervous system disorder can be a Parkinson'sdisease-induced ENS disorder. Parkinson's disease-induced ENS disordercan be related to degeneration of dopamine ENS neurons. Symptoms of aParkinson's disease-induced ENS disorder include, e.g., constipation,nausea, vomiting, and the like. In some embodiments, a subject to betreated according to a method of the invention is diagnosed with,suffering a symptom of, is suspected of having, Parkinson's disease, andfurther exhibits a symptom of an ENS disorder as described herein.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having an entericnervous system disorder can associated with Scleroderma. Scleroderma canbe characterized by hardening and tightening of the skin and connectivetissues. In some embodiments, the subject is suffering from, may bediagnosed with, may be exhibiting a symptom of, or may be suspected ofhaving gastroparesis associated with Scleroderma.

The subject may be suffering from, may be diagnosed with, may beexhibiting a symptom of, or may be suspected of having adiabetes-associated enteric nervous system disorder. Thediabetes-associated enteric nervous system disorder can be adiabetes-associated gastroparesis. The subject may be suffering from,may be diagnosed with, may be exhibiting a symptom of, or may besuspected of having an enteric nervous system disorder associated withmultiple sclerosis.

Other diseases and clinical conditions that can cause an enteric nervoussystem disorder such as gastroparesis include, e.g., cancer,hypothyroidism, hyperthyroidism, hyperparathyroidism, adrenalinsufficiency (Addison's disease), gastric ulcer, gastritis,post-gastric surgery, such as, e.g., vagotomy (resection of the vagusnerve), antrectomy (resection of a portion of the stomach distal to theantrum of the stomach), subtotal gastrectomy (resection of a gastrictumor), gastrojejunostomy (a surgical procedure that connects two lumensof the GI tract, such as a proximal segment of stomach and a segment ofthe small intestine), fundoplication (a surgical procedure that wraps anupper portion of the stomach around a lower end of the esophagus),polymyositis (a persistent inflammatory muscle disease that can causemuscle weakness), muscular dystrophy (a disease that can causeprogressive muscle weakness), amyloidosis (characterized by buildup ofamyloid in a tissue or organ of the subject, such as in thegastrointestinal tract), intestinal pseudo-obstruction (a condition thatcauses symptoms that are associated with bowel obstruction but whereinno bowel obstruction is found), dermatomyositis (a disease characterizedby muscular inflammation), systemic lupus erythematosus (a systemicautoimmune disease that can affect various tissues of the body,including the nervous system), eating disorders such as, e.g., anorexiaand bulimia, depression, paraneoplastic syndrome, and high cervical cordlesions (e.g., lesions at spinal cord C4 or above).

The subject can be suffering a symptom of an enteric nervous systemdisorder. Exemplary symptoms are described herein. In some embodiments,the symptom is nausea and/or vomiting. In some embodiments, the cause ofthe symptom is unknown (e.g., unexplained nausea). In some embodiments,the symptom is a chronic or recurrent symptom. The subject may, forexample, experience the symptom for over 3 days, over 5 days, over 1week, over 2 weeks, over 4 weeks, over 1 month, over 2 months, over 3months, over 4 months, over 5 months, over 6 months, over 7 months, over8 months, over 9 months, over 10 months, over 11 months, over 12 months(1 year), over 1.5 years, over 2 years, over 3 years, over 4 years, over5 years, over 6 years, over 7 years, over 8 years, over 9 years, or over10 years. The subject may experience the symptom 1, 2, 3, 4, 5, 6, 7, 8,8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, or more than 31 times a month.

In some embodiments, the symptom is a side effect of a drugadministration and/or a treatment regimen. The treatment regimen can bea treatment regimen for cancer. Exemplary treatment regimens for cancerwhich are known to induce a symptom of an enteric nervous systemdisorder include chemotherapy. Exemplary chemotherapeutic agents whichcan induce nausea and/or vomiting in a subject include, but are notlimited to, cisplatin, cyclophosphamide, carmustine, dicarbazine,actinomycin D, mechlorethamine, carboplatin, doxorubicin, epirubicin,irinotecan, methotrexate, and dacarbazine. In some embodiments, theadministered drug causing the symptom is an anesthetic drug. Theanesthetic drug can be a general anesthetic. Exemplary generalanesthetic drugs include, but are not limited to, propofol, fentanyl,rocuronium, nitrous oxide, physostigmine and opioids. In someembodiments, the compounds described herein are used in the treatment ofpost-operative nausea and/or vomiting (PONV).

The subject may be, e.g., a mouse, a rat, a hamster, a gerbil, a dog, acat, a primates such as, e.g., a monkey or human. In some embodiments,the subject is a human. The subject may be an adult, a child, or aninfant. The subject can be of any age.

Use of the Compounds

Compounds described herein can be safely administered to a subject.Compounds described herein can be administered without necessarilyincreasing risk of developing a deleterious cardiac side effect. Forexample, compounds described herein may not increase risk of modulatingcardiac action potential, and/or may not increase risk of inducing longQT syndrome, and/or may not increase risk of cardiac arrest, and/or maynot increases risk of sudden death by cardiac arrest.

The subject may be safely administered an effective amount of a compounddescribed herein for an unlimited amount of time. The subject may besafely administered an effective amount of the compound acutely orchronically. For example, the subject may be safely administered aneffective amount of the compound once, for one day, for 2 days or more,for 3 days or more, for four days or more, for five days, for over fivedays, for over six days, for over seven days (1 week), for over 2 weeks,for over 3 weeks, for over 4 weeks, for over 5 weeks, for over 6 weeks,for over 7 weeks, for over 8 weeks, for over 9 weeks, for over 10 weeks,for over 11 weeks, for over 12 weeks, for over 3 months, for over 4months, for over 5 months, for over 6 months, for over 7 months, forover 8 months, for over 9 months, for over 10 months, for over 11months, for over 12 months (1 year), for over 2 years, for over 5 years,or for over a decade.

Administration of a compound described herein may confer an acceptablerisk that the subject will develop an unwanted cardiac side effect. Riskof compound administration on developing such unwanted cardiac sideeffect can be determined by any means known in the art, or as describedherein. For example, risk can be determined by comparing the incidenceof sudden death in a population of subjects administered the compoundsas compared to incidence of sudden death in a population of controlsubjects that have not been administered the compounds. Risk can bedetermined by tracking the number of subjects administered the compoundwho experienced the unwanted cardiac side effect, and the number ofsubjects administered the compound who did not experience the unwantedcardiac side effect. For example, if a=the number of subjectsadministered the compound who experienced the unwanted cardiac sideeffect, and b=the number of subjects administered the compound who didnot experience the unwanted cardiac side effect, the risk ofexperiencing the unwanted cardiac side effect conferred by beingadministered the compound can be calculated as a/(a+b). Relative risk(RR) may be used to compare the risk of developing an unwanted cardiacside effect conferred by administration of the compound to the risk ofdeveloping the unwanted cardiac side effect in a population of subjectsthat have not been administered the compound. For example, if a=thenumber of subjects administered the compound who experienced theunwanted cardiac side effect, b=the number of subjects administered thecompound who did not experience the unwanted cardiac side effect, c=thenumber of subjects not administered the compound who experienced theunwanted cardiac side effect, and d=the number of subjects notadministered the compound who did not experience the unwanted cardiacside effect, RR conferred by administration of the compound can becalculated as a/(a+b)/(c/(c+d). For other example, risk can bedetermined by calculating an odds ratio.

The RR of administration of a compound described herein with suddencardiac death can be less than 3.8, less than 3.7, less than 3.6, lessthan 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1,less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, lessthan 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7,less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the RR of administration of metopimazine withsudden cardiac death is less than 3.8, less than 3.7, less than 3.6,less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, lessthan 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2,less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, lessthan 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the RR of administration of metopimazine acid withsudden cardiac death is less than 3.8, less than 3.7, less than 3.6,less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, lessthan 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2,less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, lessthan 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the RR of administration of carbidopa with suddencardiac death is less than 3.8, less than 3.7, less than 3.6, less than3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, lessthan 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6,less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, lessthan 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2,less than 1.1, less than 1.05, about 1, or less than 1.

The odds ratio of administration of a compound described herein withsudden cardiac death can be an acceptable odds ratio. The term oddsratio (OR) generally refers to a measure of association between anexposure (e.g., exposure to a drug) and an outcome (e.g., sudden cardiacdeath). The OR can represent the odds that the outcome will occur givena particular exposure, as compared to the odds of the outcome occurringin the absence of that exposure. Odds ratios can be used in case-controlstudies, as well as in cross-sectional and cohort study design studies.For example, if a=the number of subjects administered the compound whoexperienced the unwanted cardiac side effect, b=the number of subjectsadministered the compound who did not experience the unwanted cardiacside effect, c=the number of subjects not administered the compound whoexperienced the unwanted cardiac side effect, and d=the number ofsubjects not administered the compound who did not experience theunwanted cardiac side effect, OR conferred by administration of thecompound can be calculated as ad/bc.

The OR of administration of a compound described herein with suddencardiac death can be less than 3.8, less than 3.7, less than 3.6, lessthan 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1,less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, lessthan 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7,less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the OR of administration of metopimazine withsudden cardiac death is less than 3.8, less than 3.7, less than 3.6,less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, lessthan 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2,less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, lessthan 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the OR of administration of metopimazine acid withsudden cardiac death is less than 3.8, less than 3.7, less than 3.6,less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, lessthan 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2,less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, lessthan 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

In some embodiments, the OR of administration of carbidopa with suddencardiac death is less than 3.8, less than 3.7, less than 3.6, less than3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, lessthan 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6,less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, lessthan 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2,less than 1.1, less than 1.05, about 1, or less than 1.

Unlike other dopamine modulating drugs previously indicated for thetreatment of ENS, the compounds described herein for use in thetreatment of ENS are peripherally restricted compounds. Accordingly,such compounds can be safely administered to a subject withoutincreasing risk in the subject for developing motor-related dysfunctionmediated by brain dopaminergic signaling. For example, such compoundscan be safely administered to a subject without increasing risk in thesubject for developing an extrapyramidal side effect. Exemplaryextrapyramidal side effects include, e.g., tardive dyskinesia(involuntary asymmetrical movements of the muscles), dystonia(characterized by sustained muscle contractions), akinesia (lack ofmovement), akathisia (feeling of motor restlessness), bradykinesia(slowed movements), stiffness, and tremor, twisting and/or repetitivemovements, abnormal postures, muscle spasms, e.g., muscle spasms of theneck (torticullis), muscle spasms of the eyes (oculogyric crisis) tonguespasms, spasms of the jaw, and the like. Extrapyramidal symptoms can beassessed by any means known in the art or otherwise described herein.For example, extrapyramidal symptoms may be assessed using theSimpson-Angus Scale (SAS) and/or the Barnes Akathisia Rating Scale(BARS). In some embodiments the odds ratio of administration of thecompounds described herein for use in treating an enteric nervous systemdisorder with incidence of an extrapyramidal side effect is less than 4,less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, lessthan 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6,less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, lessthan 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2,less than 1.1, less than 1.05, about 1, or less than 1. In someembodiments, the odds ratio of administration of metopimazine withincidence of an extrapyramidal side effect is less than 4, less than3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, lessthan 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0,less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, lessthan 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6,less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than1.1, less than 1.05, about 1, or less than 1. In some embodiments, theodds ratio of administration of metopimazine acid with incidence of anextrapyramidal side effect is less than 4, less than 3.9, less than 3.8,less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, lessthan 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4,less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, lessthan 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.05,about 1, or less than 1. In some embodiments, the odds ratio ofadministration of carbidopa with incidence of an extrapyramidal sideeffect is less than 4, less than 3.9, less than 3.8, less than 3.7, lessthan 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2,less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, lessthan 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8,less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or less than1.

The compounds of the invention can promote gastric motility uponadministration to the subject. Such compounds may promote gastricmotility by, for example, reducing dopamine D2-receptor mediatedsignaling in an enteric neuron of the subject. For example, themetopimazine and metopimazine acid can antagonize dopamine D2 receptorsin an enteric neuron of the subject. For other example, a dopaminedecarboxylase inhibitor, e.g., carbidopa, can reduce peripheral dopaminesynthesis and thus may reduce dopamine neurotransmission of an entericneuron.

Gastric motility can be assessed by any means known to those of skill inthe art or otherwise described herein. For example, gastric motility canbe assessed by antral manometry, or by methods useful in the diagnosisof gastroparesis. Exemplary methods useful in the diagnosis ofgastroparesis are described herein.

Administration of the compounds as described herein can improve gastricmotility as compared to a control subject and/or control population. Thecontrol subject can be an individual that has not been administered acompound described herein. A control population can be a plurality ofindividuals that have not been administered a compound described herein.The control subject can be a subject that is suffering from, that hasbeen diagnosed with, be suspected of having, or exhibiting a symptom ofan ENS disorder, that is not administered a compound as describedherein. The control subject does not necessarily need to be a differentindividual, but may be the same subject at a time point prior toreceiving a dose of a compound as described herein. The control subjectmay be the same subject at a time point subsequent to receiving a doseof a compound as described herein, after a sufficient time has passedsuch that the compound is no longer acting in the subject. The controlsubject can be a different subject. In some embodiments, administrationof a the compound increases gastric motility by at least 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, orover 100% as compared to a control subject.

In some embodiments, administration of a compound described herein iseffective in treating a symptom of an enteric nervous system disorder inthe subject. Exemplary symptoms are described herein. The symptom may beselected from the group consisting of nausea, vomiting, delayed gastricemptying, diarrhea, abdominal pain, gas, bloating, gastroesophagealreflux, reduced appetite, weight loss, and constipation. In particularcases, administration of a compound described herein reduces nausea inthe subject. Administration of a compound as described herein may reduceseverity of any of the symptoms described herein. In some cases,administration of a compound as described herein reduces symptomseverity by 1-5%, 2-10%, 5-20%, 10-30%, 20-50%, 40-70%, 50-80%, 70-90%,80-95%, 90-100%. In some cases, administration of a compound asdescribed herein reduces symptom severity by at least 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%,70%, 80%, 90%, or more than 90%.

Administration of a compound as described herein may reduce frequency ofonset of a symptom. In some cases, administration of a compound asdescribed herein reduces frequency of symptom onset by 1-5%, 2-10%,5-20%, 10-30%, 20-50%, 40-70%, 50-80%, 70-90%, 80-95%, 90-100%. In somecases, administration of a compound as described herein reducesfrequency of symptom onset by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, ormore than 90%. In some cases, administration of a compound as describedherein reduces frequency of symptom onset to less than 1 episode a day,less than 1 episode a week, less than 2 episodes a month, less than 1episode a month, less than 1 episode every 2 months, less than 1 episodeevery 3 months, less than 1 episode every 4 months, less than 1 episodeevery 5 months, less than 1 episode every 6 months, less than 1 episodeevery 7 months, less than 1 episode every 8 months, less than 1 episodeevery 9 months, less than 1 episode every 10 months, less than 1 episodeevery 11 months, or less than 1 episode every 12 months (1 year).

Exemplary Compounds

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. Prodrugs are often useful because, in some situations, theymay be easier to administer than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent isnot. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. An example, without limitation, of aprodrug would be a compound described herein, which is administered asan ester (the “prodrug”) to facilitate transmittal across a cellmembrane where water solubility is detrimental to mobility but whichthen is metabolically hydrolyzed to the carboxylic acid, the activeentity, once inside the cell where water-solubility is beneficial. Afurther example of a prodrug might be a short peptide (polyaminoacid)bonded to an acid group where the peptide is metabolized to reveal theactive moiety. In certain embodiments, upon in vivo administration, aprodrug is chemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound. To produce a prodrug, a pharmaceutically active compoundcan be modified such that the active compound will be regenerated uponin vivo administration. The prodrug can be designed to alter themetabolic stability or the transport characteristics of a drug, to maskside effects or toxicity, to improve the flavor of a drug or to alterother characteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs can be useful because, in some situations, they may be easierto administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may have improved solubility in pharmaceutical compositions overthe parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol, 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein in their entirety.

Sites on the aromatic ring portion of compounds of any of Formula I-XIcan be susceptible to various metabolic reactions, thereforeincorporation of appropriate substituents on the aromatic ringstructures, such as, by way of example only, halogens can reduce,minimize or eliminate this metabolic pathway. Compounds described hereininclude isotopically-labeled compounds, which are identical to thoserecited in the various formulas and structures presented herein, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto the present compounds include isotopes of hydrogen, carbon,nitrogen, oxygen, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certain isotopically-labeledcompounds described herein, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Further, substitution withisotopes such as deuterium, i.e., ²H, can afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formed)by reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, andthe like; or with an organic acid such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like.

The corresponding counterions of the pharmaceutically acceptable saltsmay be analyzed and identified using various methods including, but notlimited to, ion exchange chromatography, ion chromatography, capillaryelectrophoresis, inductively coupled plasma, atomic absorptionspectroscopy, mass spectrometry, or any combination thereof.

The salts can be recovered by using at least one of the followingtechniques: filtration, precipitation with a non-solvent followed byfiltration, evaporation of the solvent, or, in the case of aqueoussolutions, lyophilization.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

It should be understood that a reference to a salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UVIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Any of the structures herein can encompass compounds that differ by thepresence of one or more isotopically enriched atoms. For example,compounds having a structure herein, except for the substitution of oneor more hydrogens by a deuterium and/or tritium are within the scope ofthe invention. For other example, compounds having a structure herein,except for the substitution of a one or more carbons by 13C- or14C-enriched carbon are within scope of this invention. The compounds ofthe present invention may also contain unnatural portions of atomicisotopes at one or more of atoms that constitute such compounds.

Compounds utilized in embodiments of the invention may comprise aphenothiazine group, may be peripherally restricted upon administrationto a subject and may not substantially inhibit an hERG channel.Compounds comprising a phenothiazine group may be referred to herein as“phenothiazines” or “phenothiazine compounds”. The phenothiazinecompound which is peripherally restricted upon administration to asubject and does not substantially inhibit an hERG channel may be acompound of Formula I:

wherein R₁ and R₂ are each independently selected from the groupconsisting of H, cyano, nitro, azido, halo, —CF₃, unsubstituted C₁-C₄alkyl, —SR₄, —S(O)R₄, —S(O)₂R₄, —NR₄R₄, —OR₄ and C₁-C₄ alkyl substitutedwith one or more substituents selected from the group consisting ofhalo, —OR₄, —SR₄, —S(O)R₄, —S(O)₂R₄, or —OR₄; each R₄ is independentlyselected from H and C₁-C₄ alkyl; L a bond or C₁-C₁₀ alkyl optionallysubstituted with —OR₄ or NR₄R₄; and R₃ is H, —NR₄R₄, or C₃-C₇heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and Sin the ring, wherein the heterocycloalkyl group if present is optionallysubstituted with one or more substituents selected from the groupconsisting of aryl, R₄, —CO₂H, —CO₂R₄, —C(O)NR₄R₄ and C₁-C₄ alkyloptionally substituted with —OR₄ or —NR₄R₄.

The compound of Formula I may be a compound of Formula II:

wherein R₁ is H, halo, —CF₃, unsubstituted C₁-C₄ alkyl, —SR₄, —S(O)R₄,—S(O)₂R₄, or —OR₄; each R₄ is independently selected from H and C₁-C₄alkyl; L is a bond or C₁-C₆ alkyl; and R₃ is H, —NR₄R₄, or C₃-C₇heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and Sin the ring, wherein the heterocycloalkyl group if present is optionallysubstituted with —CO₂H, —CO₂R₄, —C(O)NR₄R₄, or C₁-C₄ alkyl optionallysubstituted with —OR₄, —NR₄R₄.

In particular embodiments, the compound of Formula II is a compound ofFormula III:

The compound of Formula III is referred to herein as “metopimazine” or1-[3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-piperidine-4-carboxamide.Metopimazine, and methods of making metopimazine, are described inDE1092476, hereby incorporated by reference. Metopimazine can beobtained from a variety of commercial sources (CAS registry number0014008-44-7). By way of example only, metopimazine can be obtained fromABI Chemicals (#AC2A05HFH), AKos (#AKOS005065914), Biochempartner (#BCP9000716), Molport (#MolPort-003-808-703), Santa Cruz Biotechnology (#sc-211901), and Tractus Company Limited (#TX-013443).

In particular embodiments, the compound of Formula II is a compound ofFormula IV:

A compound of Formula (IV) can be referred to as “metopimazine acid”.Metopimazine acid can be obtained from a variety of commercial sources,such as, e.g., Santa Cruz Biotechnology, Inc., (catalog # SC211902), TLCPharmachem (#M-363), CacheSyn (#CSTM363), and Toronto Research Chemicals(#M338767).

Also provided herein are prodrugs of metopimazine and/or metopimazineacid. Exemplary prodrugs are described herein.

Prodrugs of the invention can include ester, amide, or amino acidprodrug forms of metopimazine and/or metopimazine acid. In someembodiments, the prodrug of metopimazine acid is a compound of Formula(V):

wherein X is O or NH; R₅ is C₁-C₆ linear or branched alkyl, benzyl,CH₂OH, CH₂CH₂OH, or CH₂CH₂SMe; Y and Z are both hydrogen or together canbe a carbonyl oxygen; R₆ is OH, OR₇, or NR₈R₉; and R₇, R₈, and R₉ areindependently C₁-C₄ linear or branched alkyl.

Alternatively, the prodrug of metopimazine acid can comprise an acetaland/or aminal moiety. For example, a prodrug of metopimazine acid can bedescribed by formula (VI):

wherein R₁₀ is C₁-C₄ linear or branched alkyl; and R₁₁ is C₁-C₆ linearor branched alkyl, phenyl, or C₄-C₇ cycloalkyl.

Alternatively, the prodrug of metopimazine acid can comprise an estermoiety. An exemplary ester prodrug of metopimazine acid is ethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate(Formula VII):

Another exemplary ester prodrug of metopimazine acid is[2-(dimethylamino)-2-oxo-ethyl]1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate(Formula VIII)

Yet another exemplary ester prodrug of metopimazine acid is2-dimethylaminoethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate(Formula IX):

The prodrug of metopimazine acid can comprise an amino acid moiety. Anexemplary amino acid prodrug of metopimazine acid is1-(2-methylpropanoyloxyl)ethyl1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylate(Formula X):

Another exemplary prodrug of metopimazine acid is2-[[1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carbonyl]amino]propanoicacid (Formula XI):

Dopamine Decarboxylase Inhibitors

Compounds utilized in embodiments of the invention may include dopaminedecarboxylase inhibitors. The dopamine decarboxylase inhibitor can be aperipherally restricted dopamine decarboxylase inhibitor. In someembodiments, the peripherally restricted dopamine decarboxylaseinhibitor is carbidopa. The carbidopa may be S-carbidopa. The carbidopamay be L-carbidopa. The carbidopa may be a mixture of S-carbidopa andL-carbidopa. The IUPAC systemic name for carbidopa is(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid.Carbidopa is available from a variety of commercial vendors, such as,e.g., Aton Pharma, Inc. Pharmaceutical compositions comprising carbidopacan be manufactured by a variety of pharmaceutical companies, such as,by way of example only, Aton Pharma, Inc., Bristol-Myers Squibb Co.,Medisca, Inc., and Merck & Company. In some embodiments, theperipherally restricted dopamine decarboxylase inhibitor is Benserazide,Methyldopa, or α-Difluoromethyl-DOPA (DFMD, DFM-DOPA). Pharmaceuticalcompositions comprising Benserazide can be manufactured by a variety ofpharmaceutical companies, such as, by way of example only, Roche.Pharmaceutical compositions comprising methyldopa can be manufactured bya variety of pharmaceutical companies, such as, by way of example only,Merck and Company. α-Difluoromethyl-DOPA is described in Journal ofNeurochemistry 31(4):927-932, which is hereby incorporated by referencein its entirety.

Peripherally Restricted Dopamine D2 Receptor Antagonists

Compounds utilized in embodiments of the invention may includeperipherally restricted D2 receptor antagonists which exhibit minimalhERG channel inhibition. Compounds may be identified as being dopamineD2 receptor antagonists by any means known in the art, or otherwisedescribed herein. In some cases, a compound can be identified as a D2receptor antagonist via a functional antagonist assay. A typicalfunctional antagonist assay measures the ability of a putativeantagonist to inhibit receptor signaling mediated by an agonist. Forexample, a compound can be identified as a D2 receptor antagonist if thecompound inhibits D2 receptor-mediated signaling. Exemplary D2receptor-mediated signaling events include, but are not limited to, cAMPsignaling, ERK phosphorylation, and β-arrestin translocation. Such D2receptor-mediated signaling events can be assayed using methods known inthe art. For example, D2 receptor-mediated cAMP signaling can beassessed using the GloSensor™ cAMP Assay (Promega, Inc.). For otherexample, D2 receptor-mediated ERK phosphorylation can be determined by,e.g., western blot analysis. In some cases, a compound can be identifiedas a D2 receptor antagonist via radioligand binding assay. In someembodiments, the dopamine D2 receptor antagonist is not domperidone. Insome embodiments, the dopamine D2 receptor antagonist is not a compoundof Formula (Y):

wherein X is —CH═CH—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—CH₂—, —CH₂—S—,—S—, or —O—, and R is a 5- or 6-membered nitrogen heterocyclic ringoptionally fused to a benzo group.

The D2 receptor antagonist utilized in a method of the invention canhave a potency. The potency can be defined by its IC50 value, whichdenotes the concentration of antagonist needed to elicit half inhibitionof the maximum biological response of an agonist. In some embodiments,the IC50 of the dopamine D2 receptor antagonist is 10⁻¹² M to 10⁻⁵ M. Insome embodiments, the dopamine D2 receptor antagonist is a D2/D3receptor antagonist.

A D2 receptor antagonist can be identified as a peripherally restrictedmolecule (e.g., as not crossing an intact blood brain barrier) by anymeans known in the art or otherwise described herein. For example, alabeled compound may be administered peripherally to a subject, andmonitored for detection of the labeled compound in a forebrain ormidbrain brain tissue. Detection of the labeled compound in a forebrainor midbrain brain tissue can be determined by ex vivo and/or in vivomethods known to those of skill in the art, such as, by way ofnon-limiting example, PET imaging, immunohistochemistry, radioligandbinding, and the like. For other example, capability of a molecule tocross a blood brain barrier can be determined by an in vitro assay. Anexemplary in vitro assay is described in U.S. Pat. No. 8,417,465, whichis hereby incorporated by reference.

hERG channel inhibition can be determined by any means known in the artor otherwise described herein. hERG channel inhibition can be assessedin vitro, for example, by utilizing hERG expressing cultured cells.hERG-expressing cultured cells for the purposes of assessing hERGchannel inhibition are available from a number of commercial vendors,such as, e.g., Life Technologies, Cyprotex, and the like. hERG channelinhibition can be assessed by a variety of means known in the art,including, e.g., voltage clamp studies, hERG binding assays, and thelike. Voltage clamp studies can employ the use of commercially availablehigh throughput systems. Exemplary high-throughput systems are describedin, e.g., U.S. Pat. No. 8,329,009, and US Patent Application Pub. No.20020164777, which are hereby incorporated by reference. hERG bindingassays can include competition and/or saturation binding assays using^(3H)dofetilide. Such assays are described in J Pharmacol ToxicolMethods. 2004 November-December; 50(3): 187-99, which is herebyincorporated by reference. hERG channel inhibition can be determined byin vivo studies, for example, by assessment of cardiac action potentialsin large animal models, e.g., canines.

Minimal hERG inhibition can be evidenced by an IC50 that is higher than0.1 μM, higher than 0.2 μM, higher than 0.3 μM, higher than 0.4 μM,higher than 0.5 μM, higher than 0.6 μM, higher than 0.7 μM, higher than0.8 μM, higher than 0.9 μM, higher than 1 μM, higher than 2 μM, higherthan 3 μM, higher than 4 μM, higher than 5 μM, higher than 6 μM, higherthan 7 μM, higher than 8 μM, higher than 9 μM, higher than 10 μM, higherthan 15 μM, higher than 20 μM, higher than 30 μM, higher than 40 μM,higher than 50 μM, higher than 60 μM, higher than 70 μM, higher than 80μM, higher than 90 μM, or higher than 100 μM.

Minimal hERG inhibition can also be evidenced by measuring, at any givendose of a drug, the % inhibition of hERG-mediated tail current.hERG-mediated tail current can be measured by voltage clamp studies,e.g., by patch clamps studies. For example, hERG-mediated tail currentcan be measured in an hERG-expressing cell prior to contact of the cellwith a test agent. hERG-mediated tail current can then be measured inthe hERG-expressing cell after contact with a dose of the test agent.The differences between the hERG-mediated tail current before and afteradministration of the test agent can be used to determine the extent towhich the test agent inhibited hERG-mediated tail current. A suitableagent for use in the invention can, at a 1 μM dose, inhibithERG-mediated tail current by less than 50%, less than 45%, less than40%, less than 35%, less than 30%, less than 25%, less than 20%, lessthan 15%, less than 10%, less than 9%, less than 8%, less than 7%, lessthan 6%, less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than0.25%, less than 0.2%, less than 0.15%, or less than 0.1%. A suitableagent for use in the invention can, at a 100 nM dose, inhibithERG-mediated tail current by less than 20%, less than 15%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1%, less than0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%,less than 0.15%, or less than 0.1%. In some embodiments, metopimazinecan, at a 3 μM dose, inhibit hERG-mediated tail current by less than50%, less than 45%, less than 40%, less than 35%, less than 30%, lessthan 25%, less than 20%, less than 15%, less than 10%, less than 9%,less than 8%, less than 7%, less than 6%, less than 5%, less than 4%,less than 3%, less than 2%, less than 1%, less than 0.5%, less than0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15%,or less than 0.1%. In some embodiments, metopimazine acid can, at a 10μM dose or higher, inhibit hERG-mediated tail current by less than 50%,less than 45%, less than 40%, less than 35%, less than 30%, less than25%, less than 20%, less than 15%, less than 10%, less than 9%, lessthan 8%, less than 7%, less than 6%, less than 5%, less than 4%, lessthan 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%,less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15%, orless than 0.1%.

Exemplary Pharmaceutical Compositions

In general, the methods of the invention utilize pharmaceuticalcompositions comprising one or more of the compounds described hereinfor the treatment of an enteric nervous system disorder. In someembodiments, the pharmaceutical composition comprises a compound ofFormula I. In some embodiments, the pharmaceutical composition comprisesa compound of Formula II. In some embodiments, the pharmaceuticalcomposition comprises a compound of Formula III. In some embodiments,the pharmaceutical composition comprises a compound of Formula IV. Insome embodiments, the pharmaceutical composition comprises a compound ofany of Formulas V-XI. In some embodiments, the pharmaceuticalcomposition comprises carbidopa. In some embodiments, the pharmaceuticalcomposition comprises a peripherally restricted dopamine D2 receptorantagonist that does not inhibit hERG activity. In some embodiments, thecomposition comprises a therapeutically effective amount of any of thecompounds described herein for the treatment of an enteric nervoussystem disorder.

Pharmaceutical compositions utilized in the methods of the invention mayinclude a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable carrier for the present compositions may include, but are notlimited to, amino acids, peptides, biological polymers, non-biologicalpolymers, simple sugars or starches, inorganic salts, and gums, whichmay be present singly or in combinations thereof. The peptides used inthe acceptable carrier may include, e.g., gelatin and/or albumin.Cellulose or its derivatives may be used in the pharmaceuticallyacceptable carrier. The sugar used in the acceptable carrier may belactose and/or glucose. Other useful sugars which may be utilized in thepharmaceutical compositions include but are not limited to, fructose,galactose, lacticol, maltitol, maltose, mannitol, melezitose,myoinositol, palatinate, raffinose, stachyose, sucrose, tehalose,xylitol, hydrates thereof, and combinations of thereof. Binders may beincluded in the pharmaceutically acceptable carrier. Examples of bindersinclude, but are not limited to, starches (for example, corn starch orpotato starch), gelatin; natural or synthetic gums such as acacia,sodium alginate, powdered tragacanth, guar gum, cellulose or cellulosederivatives (for example, methycellulose, ethyl cellulose, celluloseacetate); microcrystalline cellulose, polyvinyl pyrrolidone, andmixtures thereof. Inorganic salts used in the acceptable carrier may bea magnesium salt, for example, magnesium chloride or magnesium sulfate.Other inorganic salts may be used, for example, calcium salts. Examplesof calcium salts include, but are not limited to, calcium chloride,calcium sulfate. Other examples of substances which may be used in thepharmaceutically acceptable carrier include, but are not limited to,vegetable oils, such as peanut oil, cottonseed oil, olive oil, corn oil;polyols such as glycerin, propylene glycol, polyethylene glycol;pyrogen-free water, isotonic saline, phosphate buffer solutions;emulsifiers, such as the Tweens®; wetting agents, lubricants, coloringagents, flavoring agents, preservatives.

The term “wetting agents” may be used interchangeably with“surfactants”, and refers to substances that lower the surface tensionof a liquid, thus allowing the liquid to spread more easily. Surfactantwhich can be used to form pharmaceutical compositions and dosage formsof the invention include, but are not limited to, hydrophilicsurfactants, lipophilic surfactants, and mixtures thereof. That is, amixture of hydrophilic surfactants may be employed, a mixture oflipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. A useful parameter that may be usedto characterize the relative hydrophilicity and hydrophobicity ofnon-ionic amphiphilic compounds is the hydrophilic-lipophilic balance(“HLB” value). Surfactants with lower HLB values are more hydrophobic,and have greater solubility in oils, while surfactants with higher HLBvalues are more hydrophilic, and have greater solubility in aqueoussolutions. Hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are generally considered to be compounds having an HLB valueequal to or less than about 10. However, HLB value of a surfactantmerely provides a rough guide generally used to enable formulation ofindustrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts, fattyacid derivatives of amino acids, glyceride derivatives of amino acids,fusidic acid salts, oligopeptides, and polypeptides, oligopeptides, andpolypeptides, lecithins and hydrogenated lecithins, lysolecithins andhydrogenated lysolecithins, phospholipids and derivatives thereof, fattyacid salts, lysophospholipids and derivatives thereof, carnitine fattyacid ester salts, salts of alkylsulfates, sodium docusate,acylactylates, mono- and di-acetylated tartaric acid esters of mono- anddi-glycerides, succinylated mono- and di-glycerides, citric acid estersof mono- and di-glycerides, and mixtures thereof.

Within the aforementioned group, ionic surfactants include, but are notlimited to, lecithins, lysolecithin, phospholipids, lysophospholipidsand derivatives thereof, carnitine fatty acid ester salts, fatty acidsalts, salts of alkylsulfates, sodium docusate, acylactylates, mono- anddi-acetylated tartaric acid esters of mono- and di-glycerides,succinylated mono- and di-glycerides, citric acid esters of mono- anddi-glycerides, and mixtures thereof.

Ionic surfactants may be the ionized forms of lactylic esters of fattyacids, lecithin, lysolecithin, phosphatidylethanolamine,phosphatidylcholine, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine, lysophosphatidylserine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, linoleate, linolenate,stearate, ricinoleate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides, alkylthioglucosides, alkylmaltosides, laurylmacrogolglycerides, polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols, polyethylene glycol glycerol fatty acid esters,polyoxyalkylene alkyl phenol fatty acid esters such as polyethyleneglycol fatty acids monoesters and polyethylene glycol fatty acidsdiesters, polyglycerol fatty acid esters,polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof,polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycolsorbitan fatty acid esters, hydrophilic transesterification products ofa polyol with at least one member of the group consisting of glycerides,vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols,polyoxyethylene sterols and derivatives or analogues thereof,polyoxyethylated vitamins and derivatives thereof, polyethylene glycolsorbitan fatty acid esters and hydrophilic transesterification productsof a polyol with at least one member of the group consisting oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20oleate, PEG-20 laurate, PEG-32 dilaurate, PEG-32 laurate, PEG-20dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryllaurate, PEG-20 trioleate, PEG-30 glyceryl laurate, PEG-20 glycerylstearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-50 hydrogenated castoroil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenatedcastor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-40 sorbitanoleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleylether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrosemonostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, but are not limited to, fattyalcohols, glycerol fatty acid esters, acetylated glycerol fatty acidesters, lower alcohol fatty acids esters, propylene glycol fatty acidesters, sorbitan fatty acid esters, polyethylene glycol sorbitan fattyacid esters, sterols and sterol derivatives, polyoxyethylated sterolsand sterol derivatives, polyethylene glycol alkyl ethers, sugar ethers,sugar esters, hydrophobic transesterification products of a polyol withat least one member of the group consisting of glycerides, vegetableoils, hydrogenated vegetable oils, fatty acids and sterols, oil-solublevitamins/vitamin derivatives, lactic acid derivatives of mono- anddi-glycerides, and mixtures thereof. Within this group, preferredlipophilic surfactants include glycerol fatty acid esters, propyleneglycol fatty acid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member of thegroup consisting of vegetable oils, hydrogenated vegetable oils, andtriglycerides.

Lubricants that may be used in the pharmaceutical composition include,but are not limited to, agar, calcium stearate, magnesium stearate,mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethylaureate, or mixtures thereof. Additionallubricants include, by way of example, a syloid silica gel, a coagulatedaerosol of synthetic silica, or mixtures thereof. A lubricant canoptionally be added, in an amount of less than about 1 weight percent ofthe pharmaceutical composition.

The composition may include a solubilizer to ensure good solubilizationof the compound and to reduce precipitation of the compound of thepresent invention. A solubilizer may be used to increase solubility ofthe compound or other active ingredients, or may be used to maintain thecomposition as a homogeneous solution or dispersion. Examples ofsuitable solubilizers include but are not limited to, alcohols andpolyols such as ethanol, isopopropanol, polyvinyl alcohol, gelatin,mannitol, sodium carboxymethyl cellulose (CMCNa), povidone, propyleneglycol, polyethylene glycol, polyvinyl pyrolidone, glycerin,cyclodextrins or cyclodextrin derivatives, polyethylene glycol ethers ofmolecular weight averaging about 200 to about 6000, such as PEG, amidesand other nitrogen-containing compounds such as 2-pyrrolidone,2-piperidone, epsilon.-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide and polyvinylpyrrolidone, esters such as ethylpropionate, tributylcitrate, acetyl triethylcitrate, acetyl tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,triacetin, propylene glycol monoacetate, propylene glycol diacetate,ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof,β-butyrolactone and isomers thereof, and other solubilizers known in theart, such as dimethyl acetamide, dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether, water, ormixtures and/or combinations thereof.

Mixtures of solubilizers may also be used. Examples of solubilizersinclude, but not limited to, ethyl oleate, ethyl caprylate, triacetin,triethylcitrate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethyleneglycol 200-100, transcutol, propylene glycol, glycofurol and dimethylisosorbide. Particularly preferred solubilizers include sorbitol,glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propyleneglycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample, to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 75%, 100%, or up to about 200% by weight, based on the combinedweight of the drug, and other excipients. If desired, very small amountsof solubilizer may also be used, such as 5%, 2%, 1%, 0.5% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition may include one or more pharmaceutically acceptableadditives, which may include, but are not limited to, detackifiers,anti-foaming agents, buffering agents, antioxidants, polymers,preservatives, chelating agents, odorants, opacifiers, suspendingagents, fillers, plasticizers, and mixtures thereof.

In some embodiments, the pharmaceutically acceptable carrier comprisesmore than 90%, more than 80%, more than 70%, more than 60%, more than50%, more than 40%, more than 30%, more than 20%, more than 10%, morethan 9%, more than 8%, more than 6%, more than 5%, more than 4%, morethan 3%, more than 2%, more than 1%, more than 0.5%, more than 0.4%,more than 0.3%, more than 0.2%, more than 0.1%, more than 0.09%, morethan 0.08%, more than 0.07%, more than 0.06%, more than 0.05%, more than0.04%, more than 0.03%, more than 0.02%, more than 0.01%, more than0.009%, more than 0.008%, more than 0.007%, more than 0.006%, more than0.005%, more than 0.004%, more than 0.003%, more than 0.002%, more than0.001%, more than 0.0009%, more than 0.0008%, more than 0.0007%, morethan 0.0006%, more than 0.0005%, more than 0.0004%, more than 0.0003%,more than 0.0002%, or more than 0.0001% of the pharmaceuticalcomposition by w/w, w/v or v/v.

In some embodiments, the concentration of the compound in thecomposition comprises less than 100%, less than 90%, less than 80%, lessthan 70%, less than 60%, less than 50%, less than 40%, less than 30%,less than 20%, less than 10%, less than 9%, less than 8%, less than 6%,less than 5%, less than 4%, less than 3%, less than 2%, less than 1%,less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, lessthan 0.1%, less than 0.09%, less than 0.08%, less than 0.07%, less than0.06%, less than 0.05%, less than 0.04%, less than 0.03%, less than0.02%, less than 0.01%, less than 0.009%, less than 0.008%, less than0.007%, less than 0.006%, less than 0.005%, less than 0.004%, less than0.003%, less than 0.002%, less than 0.001%, less than 0.0009%, less than0.0008%, less than 0.0007%, less than 0.0006%, less than 0.0005%, lessthan 0.0004%, less than 0.0003%, less than 0.0002%, or less than 0.0001%of the pharmaceutical composition by w/w, w/v or v/v.

In some embodiments, the concentration of the compound is in the rangeof about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% toabout 20%, about 0.02% to about 29%, about 0.03% to about 28%, about0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%,about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% toabout 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6%to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about0.9% to about 12%, about 1% to about 10% of the pharmaceuticalcomposition by w/w, w/v or v/v.

In some embodiments, the concentration of the compound is in the rangeof about 0.0001% to about 5%, about 0.001% to about 4%, about 0.01% toabout 2%, about 0.02% to about 1%, or about 0.05% to about 0.5% of thepharmaceutical composition by w/w, w/v or v/v.

In some embodiments, the amount of the compound in the pharmaceuticalcomposition is about 0.00001 mg, 0.0001 mg, 0.001 mg, 0.005 mg, 0.01 mg,0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 10 mg, 12 mg,14 mg, 16 mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1 g, 1.1 g,1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 2.5 g, 3 g,3.5 g, 4 g, 4.5 g, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g.

Described below are some non-limiting examples of pharmaceuticalcompositions.

Pharmaceutical Compositions for Oral Administration

The pharmaceutical composition comprising an effective amount of acompound can be formulated for oral administration. In some embodiments,the pharmaceutical composition comprising an effective amount of acompound for oral administration is a solid pharmaceutical composition.In some embodiments, the solid pharmaceutical composition may bepresented as discrete (e.g., unit) oral dosage forms. Non-limitingexamples of discrete oral dosage forms include tablets, capsules,caplets, gelatin capsules, sustained release formulations, lozenges,thin films, lollipops, chewing gum. In some embodiments, the discreteoral dosage form is an orally disintegrating oral dosage form, such as,e.g., an orally disintegrating tablet.

Discrete oral dosage forms such as tablets may be coated by knowntechniques to delay or prolong absorption in the gastrointestinal tract,thus providing a sustained action of a longer period of time. In someembodiments, the compound is mixed with one or more inert soliddiluents, such as calcium carbonate or calcium phosphate. In someembodiments, the compound are presented as soft gelatin capsules,wherein the compound is mixed with water or an oil medium, such aspeanut oil, or olive oil, for example.

In some embodiments, the pharmaceutical composition comprising aneffective amount of a compound for oral administration is a liquidpharmaceutical composition. Non-limiting examples of liquid compositionsfor oral administration include hydrophilic suspensions, emulsions,liquids, gels, syrups, slurries, solutions, elixirs, softgels,tinctures, and hydrogels. In some embodiments, solid or liquidcompositions comprising an effective amount of a compound for oraladministration comprise various sweetening or flavoring agents, orcoloring agents. Examples of coloring agents include dyes suitable forfood such as those known as F.D. & C. dyes and natural coloring agentssuch as grape skin extract, beet red powder, beta carotene, annato,carmine, turmeric, paprika, and so forth. Derivatives, analogues, andisomers of any of the above colored compound also may be used.

Such dosage forms may be prepared by methods well known to those skilledin the art, e.g., in a pharmacy. Such methods would comprise bringingthe compound into association with the pharmaceutically acceptablecarrier.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an effective amount of a compound, sincewater may facilitate the degradation of the compounds. In someembodiments, the anhydrous pharmaceutical compositions and dosage formsof the invention are prepared using anhydrous or low moisture containingingredients. In some embodiments, the anhydrous pharmaceuticalcompositions and dosage forms of the invention are prepared under lowhumidity or low moisture conditions. The pharmaceutical compositions ofthe present invention which contain lactose may be made anhydrous ifsubstantial contact with moisture and/or humidity during manufacturing,packaging, and/or storage is expected. An anhydrous pharmaceuticalcomposition comprising an effective amount of a compound may be preparedand stored such that its anhydrous nature is maintained. For example,the anhydrous compositions may be packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits, examples of which include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Pharmaceutical Compositions for Injection or Parenteral Administration

In some embodiments, the pharmaceutical composition is formulated forparenteral administration. “Parenteral administration” generally refersto routes of administration other than the gastro-intestinal tract.Examples of parenteral administration include, but are not limited to,intravenous injection, intra-arterial injection, intrathecal injection(into the spinal cord), intratonsillary injection, subcutaneousinjection, intramuscular injection, infusion, or implantation. Infusionmay be intradermal, or subcutaneous, or through a transdermal implant.Exemplary pharmaceutical compositions for parenteral administration aredisclosed in the following references which are hereby incorporated byreference: U.S. Patent Application Pub. No 2006/0287221, U.S. Pat. Nos.5,244,925, 4,309,421, 4,158,707, and 5,164,405, all of which are herebyincorporated by reference.

Compositions formulated for parenteral administration may includeaqueous solutions and/or buffers commonly used for injection and/orinfusion. Commonly used aqueous buffers and/or solutions may include,but are not limited to sodium chloride solutions of about 0.9%,phosphate buffers, Lactated Ringer's solution, Acetated ringer'ssolution, phosphate buffered saline, citrate buffers, Tris buffers,histidine buffers, HEPES buffers, glycine buffers, N-glycylglycinebuffers, and the like. Other pharmaceutically acceptable carriers forparenteral administration may include ethanol, glycerol, propyleneglycol, cyclodextrin and cyclodextrin derivatives, vegetable oils, andthe like.

In some embodiments, pharmaceutical compositions for injection and/orinfusion contain preservatives present in amounts that effectivelyprevent or reduce microbial contamination or degradation. Variousagents, e.g., phenol, m-cresol, benzyl alcohol, parabens, chlorobutanol,methotrexate, sorbic acid, thimerosol, ethyl hydroxybenzoate, bismuthtribromophenate, methyl hydroxybenzoate, bacitracin, propylhydroxybenzoate, erythromycin, 5-fluorouracil, doxorubicin,mitoxantrone, rifamycin, chlorocresol, benzalkonium chlorides, may beused to prevent or reduce contamination.

In some embodiments, sterile solutions are prepared by incorporating thecompound of in the required amount in the appropriate solvent withvarious other ingredients as described herein, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation include but are not limited to vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

In some embodiments, the pharmaceutical composition is formulated fortopical and/or transdermal delivery. Compositions of the presentinvention can be formulated into preparations in liquid, semi-solid, orsolid forms suitable for local or topical administration. Examples offorms suitable for topical or local administration include but are notlimited to, gels, water soluble jellies, creams, lotions, suspensions,foams, powders, slurries, ointments, oils, pastes, suppositories,solutions, sprays, emulsions, saline solutions, dimethylsulfoxide(DMSO)-based solutions. In general, carriers with higher densities arecapable of providing an area with a prolonged exposure to the activeingredients. In contrast, a solution formulation may provide moreimmediate exposure of the active ingredient to the chosen area.

The pharmaceutical composition may comprise suitable solid or gel phasecarriers, which are compounds that allow increased penetration of, orassist in the delivery of, therapeutic molecules across the stratumcorneum barrier of the skin. There are many of thesepenetration-enhancing molecules known to those skilled in the art oftopical formulation. Examples of such carriers and excipients include,but are not limited to, alcohols (e.g., ethanol), fatty acids (e.g.,oleic acid), humectants (e.g., urea), glycols (e.g., propylene glycol),surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),glycerol monolaurate, sulfoxides, pyrrolidones, terpenes (e.g.,menthol), amines, amides, alkanes, alkanols, water, calcium carbonate,calcium phosphate, various sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound as described herein in controlled amounts, eitherwith or without an additional agent. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252; 4,992,445; and5,001,139; which are herein incorporated by reference.

In some embodiments, the invention provides a pharmaceutical compositioncomprising an effective amount of a compound as described herein fortransdermal delivery, and a pharmaceutical excipient suitable fordelivery by inhalation. Compositions for inhalation include solutionsand suspensions in pharmaceutically acceptable, aqueous or organicsolvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described herein. The compositions may be administered by the oral ornasal respiratory route for systemic effect. In some embodiments,compositions in preferably pharmaceutically acceptable solvents may benebulized by use of inert gases. In some embodiments, nebulizedsolutions may be inhaled directly from the nebulizing device. In otherembodiments, nebulizing device may be attached to a face mask tent orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions may be administered, preferably orally ornasally, from devices that deliver the formulation in an appropriatemanner.

Other Pharmaceutical Compositions.

The pharmaceutical compositions employed in the present invention may beformulated for intraocular (ophthalmic), rectal, sublingual, buccal, orintranasal (e.g., intrapulmonary) administration. Formulations suitablefor intraocular administration include eye drops wherein the activeingredient is dissolved or suspended in a suitable carrier, especiallyan aqueous solvent for the active ingredient. The active ingredient ispreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulationssuitable for sublingual administration, typically are formulated todissolve rapidly upon placement in the mouth, allowing the activeingredient to be absorbed via blood vessels under the tongue. Exemplarysublingual formulations include, e.g., lozenges comprising the activeingredient in a flavored basis, usually sucrose and acacia ortragacanth; pastilles comprising the active ingredient in an inert basissuch as gelatin and glycerin, or sucrose and acacia; mouthwashescomprising the active ingredient in a suitable liquid carrier; orallydisintegrating tablets which may, for example, disintegrate in less than90 seconds upon placement in the mouth; and thin films. Suchdisintegration can be measured by an in vitro dissolution test.Formulations for buccal administration can include, e.g., buccaltablets, bioadhesive particles, wafers, lozenges, medicated chewinggums, adhesive gels, patches, films, which may be delivered as anaqueous solution, a paste, an ointment, or aerosol, to name a few.Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for intrapulmonary or nasaladministration can have a particle size for example in the range of 0.1to 500 microns (including particle sizes in a range between 0.1 and 500microns in increments microns such as 0.5, 1, 30 microns, 35 microns,etc.), which is administered by rapid inhalation through the nasalpassage or by inhalation through the mouth so as to reach the alveolarsacs. Suitable formulations include aqueous or oily solutions of theactive ingredient. Formulations suitable for aerosol or dry powderadministration may be prepared according to conventional methods and maybe delivered with other therapeutic agents such as compounds heretoforeused in the treatment or prophylaxis of cancerous infections asdescribed below. A pharmacological formulation of the present inventioncan be administered to the patient in an injectable formulationcontaining any compatible carrier, such as various vehicle, adjuvants,additives, and diluents; or the compounds utilized in the presentinvention can be administered parenterally to the patient in the form ofslow-release subcutaneous implants or targeted delivery systems such asmonoclonal antibodies, vectored delivery, iontophoretic, polymermatrices, liposomes, and microspheres. Examples of delivery systemsuseful in the present invention include: U.S. Pat. Nos. 5,225,182;5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194;4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other suchimplants, delivery systems, and modules are well known to those skilledin the art.

Preparations for such pharmaceutical compositions are described in,e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Exemplary Modes of Administration

Administration of a pharmaceutical composition as described herein canbe performed by any method that enables delivery of the compound to thesite of action. The composition may be administered orally,parenterally, enterally, intraperitoneally, topically, transdermally,ophthalmically, intranasally, locally, non-orally, via spray,subcutaneously, intravenously, intratonsillary, intramuscularly,buccally, sublingually, rectally, intra-arterially, by infusion, orintrathecally. In some embodiments, the composition is administeredorally. In some cases, the oral administration may compriseadministration of any of the oral dosage forms as described herein. Theeffective amount of a compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician.

A subject can be administered a daily dosage of a compound as describedherein for the treatment of an enteric nervous system disorder. Thedaily dosage can be from about 0.01 mg/kg to about 500 mg/kg of bodyweight per day. A daily dosage for a human can be about 1, 2, 3, 4, 5,6, 7, 8, 9, 0, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 90, 100, 120, 140, 160, 180, 200, 300, 400, 500, 600, 700,800, 900, or 1000 mg. In some embodiments, the daily dosage is greaterthan 30 mg/day, greater than 35 mg/day, greater than 40 mg/day, greaterthan 45 mg/day, greater than 50 mg/day, greater than 55 mg/day, greaterthan 60 mg/day, greater than 65 mg/day, greater than 70 mg/day, greaterthan 75 mg/day, greater than 80 mg/day, greater than 85 mg/day, greaterthan 90 mg/day, greater than 95 mg/day, greater than 100 mg/day, greaterthan 150 mg/day, greater than 200 mg/day, greater than 300 mg/day,greater than 400 mg/day, greater than 500 mg/day, greater than 600mg/day, greater than 700 mg/day, greater than 800 mg/day, greater than900 mg/day, or greater than 1000 mg/day. A daily dosage of metopimazinefor a human can be, for example, greater than 30 mg/day, greater than 35mg/day, greater than 40 mg/day, greater than 45 mg/day, greater than 50mg/day, greater than 55 mg/day, greater than 60 mg/day, greater than 65mg/day, greater than 70 mg/day, greater than 75 mg/day, greater than 80mg/day, greater than 85 mg/day, greater than 90 mg/day, greater than 95mg/day, greater than 100 mg/day, greater than 150 mg/day, greater than200 mg/day, greater than 300 mg/day. A daily dosage of metopimazine acidfor a human can be, for example, greater than 30 mg/day, greater than 35mg/day, greater than 40 mg/day, greater than 45 mg/day, greater than 50mg/day, greater than 55 mg/day, greater than 60 mg/day, greater than 65mg/day, greater than 70 mg/day, greater than 75 mg/day, greater than 80mg/day, greater than 85 mg/day, greater than 90 mg/day, greater than 95mg/day, greater than 100 mg/day, greater than 150 mg/day, greater than200 mg/day, greater than 300 mg/day, greater than 400 mg/day, greaterthan 500 mg/day, greater than 600 mg/day, greater than 700 mg/day,greater than 800 mg/day, greater than 900 mg/day, or greater than 1000mg/day. A daily dosage of a peripherally restricted dopamine carboxylaseinhibitor (e.g., carbidopa) for a human can be, for example, greaterthan 30 mg/day, greater than 35 mg/day, greater than 40 mg/day, greaterthan 45 mg/day, greater than 50 mg/day, greater than 55 mg/day, greaterthan 60 mg/day, greater than 65 mg/day, greater than 70 mg/day, greaterthan 75 mg/day, greater than 80 mg/day, greater than 85 mg/day, greaterthan 90 mg/day, greater than 95 mg/day, or greater than 100 mg/day. Insome embodiments, the daily dosage is 30-50 mg/day, 40-60 mg/day, 50-80mg/day, 80-90 mg/day, 70-100 mg/day, 90-150 mg/day, 100-200 mg/day,150-300 mg/day, or 200-500 mg/day. The compound can be administered inone or more unit dosage forms and can also be administered one to ten,one to eight, one to six, one to four, one to two times daily, or onetime daily. For example, the compound can be administered four timesdaily. A unit dosage form can comprise about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 0, 12, 14, 16, 18, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 120, 140, 160,180, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg of the compound.

In some embodiments, administration may comprise infusion. In somecases, infusion may involve chronic, steady dosing. Devices for chronic,steady dosing, e.g., by a controlled pump, are known in the art,(examples may be described in U.S. Pat. No. 7,341,577, U.S. Pat. No.7,351,239, U.S. Pat. No. 8,058,251, herein incorporated by reference).

Administration of the compound may continue as long as necessary. Insome embodiments, the compound is administered for more than 1, 2, 3, 4,5, 6, 7, 14, or 28 days. In particular embodiments, the compound isadministered for more than 5 days. In some embodiments, the compound isadministered for more than 12 weeks. In some embodiments, the compoundis administered for more than 1 month, more than 2 months, more than 4months, more than 6 months, more than 1 year, more than 2 years, or morethan 5 years. In some embodiments, the compound is administered for lessthan five days.

Exemplary Combination Therapies

In some embodiments, the method comprises co-administration of anadditional agent. Additional agents may be: small molecules,nutraceuticals, vitamins, e.g., vitamin D, drugs, pro-drugs, biologics,peptides, peptide mimetics, antibodies, antibody fragments, cell ortissue transplants, vaccines, polynucleotides, DNA molecules, RNAmolecules, (i.e.—siRNA, miRNA), antibodies conjugated to drugs, toxins,fusion proteins. Agents may be delivered by vectors, including but notlimited to: plasmid vectors, viral vectors, non-viral vectors, liposomalformulations, nanoparticle formulations, toxins, therapeuticradioisotopes, etc.

In some embodiments, a method of the invention comprisesco-administration of a peripherally restricted dopamine decarboxylaseinhibitor and a compound of any of Formulas I-XI. For example, aninvention method may comprise co-administration of carbidopa and acompound of any of Formulas I-IV. In some cases, an invention methodcomprises co-administration of carbidopa and a compound of Formula IIIor IV. In some cases, an invention method comprises co-administration ofcarbidopa and a compound of Formula III. In some cases, an inventionmethod comprises co-administration of carbidopa and a compound ofFormula IV. In some cases, an invention method comprisesco-administration of carbidopa and a compound of any of Formulas V-XI.Also contemplated in the invention is a method comprisingco-administration of a peripherally restricted dopamine decarboxylaseinhibitor and a peripherally restricted dopamine D2 receptor antagonistthat exhibits minimal hERG inhibition.

The additional agent can be an agent for use in the treatment of anenteric nervous system disorder. In some embodiments, the additionalagent is an additional anti-emetic agent (e.g., used for the treatmentof nausea and/or vomiting). The additional anti-emetic agent can be, byway of non-limiting example only, a 5-HT3 receptor antagonist, adopamine receptor antagonist, an NK1 receptor antagonist, anantihistamine, a cannabinoid, a benzodiazepine, an anticholinergicagent., a steroid, or other anti-emetic. Exemplary 5-HT3 receptorantagonists include, but are not limited to, Odansetron, Tropisetron,Granisetron, Palonosetron, Dolasetron, and Metoclopramide. Exemplarydopamine receptor antagonists include, e.g., Domperidone (Motilium),Olanzapine (Zyprexa) Droperidol, haloperidol, chlorpromazine,promethazine, prochlorperazine, Alizapride, Prochlorperazine, Sulpiride,and Metoclopramide. Exemplary NK1 receptor antagonists include, e.g.,Aprepitant, or Casopitant. Exemplary antihistamines include, e.g.,Cyclizine, Diphenhydramine (Benadryl), Dimenhydrinate (Gravol,Dramamine), Doxylamine, Meclozine (Bonine, Antivert), Promethazine(Pentazine, Phenergan, Promacot), and Hydroxyzine (Vistaril). Exemplarycannabinoids include, e.g., Cannabis, Sativex, tetrahydrocannabinol,Dronabinol, and synthetic cannabinoids such as Nabilone. Exemplarybenzodiazepines include, e.g., midazolam or lorazepam. Exemplaryanticholinergic agents include, e.g., scopolamine. Other exemplaryanti-emetics include, e.g., Trimethobenzamide, Ginger, Emetrol,Propofol, Peppermint, erythromycin, Muscimol, botulinum toxin A (e.g.,injected into the stomach to relax the pyloric muscle), and Ajwain.

The additional agent can be an agent for treatment of another disease orclinical syndrome associated with gastroparesis. Exemplary otherdiseases and clinical syndromes are described herein. The additionalagent can be an agent for treatment of diabetes. Exemplary agents forthe treatment of diabetes include, e.g., insulin. Other agents for thetreatment of diabetes are described in, for example, U.S. Pat. Nos.6,274,549, 8,349,818, 6,184,209, US Patent Application Publication No.US20070129307, and PCT Application Publication No. WO/2004/082667A1, allof which are hereby incorporated by reference.

The additional agent can be for treatment of upper and lower dysmotilitydisorders associated with Parkinson's disease. The additional agent canbe for treatment of Parkinson's disease. Exemplary agents for thetreatment of Parkinson's disease include, e.g., dopaminergic agents,MAO-A or B inhibitors such as, e.g., selegiline, COMT inhibitors such asentacapone, amantadine, stem cell transplant, and neuroprotectiveagents. Exemplary dopaminergic agents include, but are not limited tolevodopa, bromocriptine, pergolide, pramipexole, cabergoline,ropinorole, apomorphine or a combination thereof.

The additional agent can be for treatment of hypothyroidism,hyperthyroidism, or hyperparathyroidism. Exemplary agents for thetreatment of such diseases include, e.g., beta-adrenergic blockers(“beta blockers”), levothyroxine calcimimetics, estrogen, progesterone,bisphosphonates.

The additional agent can be for treatment of adrenal insufficiency.Exemplary agents for treatment of adrenal insufficiency include, e.g.,corticosteroid hormones (for example, aldosterone, fludrocortisones, andcortisol).

The additional agent can be for treatment of gastroesophageal reflux.Exemplary agents for treatment of gastroesophageal reflux include, e.g.,antacids such as, for example, proton pump inhibitors such asomeprazole, H2 receptor antagonists such as ranitidine, antacids,mosapride, sucralfate, and baclofen.

The additional agent can be for treatment of scleroderma. For example,the additional agent can be D-penicillamine, colchicine, PUVA, relaxin,cyclosporine, and EPA (omega-3 oil derivative), immunosupressants suchas, e.g., methotrexate, cyclophosphamide, azathioprine, andmycophenolate. The additional agent can be for treatment ofpolymyositis. For example, the additional agent can be a corticosteroid,e.g., prednisone, or can be an immunosuppressant.

The additional agent can be for treatment of muscular dystrophy. Forexample, the additional agent can be, e.g., a glucocorticoid receptorantagonist. Exemplary glucocorticoid receptor antagonists include, butare not limited to, mifepristone,11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one,17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one,4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-dioland4α(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol,and(11β,17β)-11-(1,3-benzodioxo-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

The additional agent can be for treatment of amyloidosis. For example,the additional agent can be an amyloid beta sheet mimic, an antioxidant,molecular chaperone, or other agent. Exemplary agents for the treatmentof amyloidosis are described in, e.g., WO/2008/141074. Exemplarymolecular chaperones include, e.g., HSP60, HSP70, HSP90, HSP100, BiP,GRP94, GRP170, calnexin and calreticulin, Protein disulfide isomerase(PDI), Peptidyl prolyl cis-trans-isomerase (PPI), trimethylamine N-oxide(TMAO), betaine, glycine betaine, glycero-phosphorylcholine,carbohydrates such as, e.g., glycerol, sorbitol, arabitol, myo-inositoland trehalose, choline, 4-Phenyl butyric acid, and taurine-conjugatedursodeoxycholic acid.

The additional agent can be for treatment of chronic idiopathicpseudoobstruction. For example, the additional agent can bePrucalopride, Pyridostigmine, Metoclopramide, cisapride, linaclotide,octreotide, cannabinoids, and erythromycin.

The additional agent can be for treatment of dermatomyositis. Forexample, the additional agent can be Prednisolone, Methotrexate,Mycophenolate (CellCept/Myfortic), intravenous immunoglobulins,Azathioprine (Imuran), Cyclophosphamide, Rituximab, and Acthar Gel.

The additional agent can be for treatment of systemic lupuserytematosus. For example, the additional agent can be renal transplant,corticosteroids, immunosupressants, Hydroxychloroquine,Cyclophosphamide, Mycophenolic acid, immunosupressants, analgesics,intravenous immunoglobins, and the like.

The additional agent can be for treatment of anorexia and/or bulimia.For example, the additional agent can be olanzapine, a tricyclicantidepressant, an MAO inhibitor, mianserin, a selective serotoninreuptake inhibitor, e.g., fluoxetine, lithium carbonate, trazodone, andbupropion, phenytoin, carbamazepine, and valproic acid, opiateantagonists such as, e.g., naloxone and naltrexone, and topiramate.

The additional agent can be for treatment of depression. For example,the additional agent can be a selective serotonin reuptake inhibitor, aserotonin and norepinephrine reuptake inhibitor, bupropion, a tricyclicantidepressant, a monoamine oxidase inhibitor, and the like. Theadditional agent can be for treatment of paraneoplastic syndrome. Theadditional agent can be for treatment of a high cervical cord lesion.For example, the additional agent can be a corticosteroid or otheranti-inflammatory medication. The additional agent can be for treatmentof multiple sclerosis. For example, the additional agent can beinterferon beta-lb, interferon beta-la, Glatiramer acetate,Mitoxantrone, natalizumab, fingolimod, teriflunomide, or cladribine.

The additional therapeutic agent can be selected from the groupconsisting of serotonin agonists, serotonin antagonists, selectiveserotonin reuptake inhibitors, anticonvulsants, opioid receptoragonists, bradykinin receptor antagonists, NK receptor antagonists,adrenergic receptor agonists, benzodiazepines, gonadotropin-releasinghormone analogues, calcium channel blockers, and somatostatin analogs.

Dosages of the additional agent and of a compound described herein foruse in the treatment of an enteric nervous system disorder can varydepending on the type of additional therapeutic agent employed, on thedisease or condition being treated and so forth. Sub-therapeutic amountsof one or both of the additional agent and the compound can be used. Thesub-therapeutic amount of one or both of the additional agent and thecompound can be a synergistically effective amount. Therapeuticallyeffective amounts of one or both of the additional agent and thecompound can be used. The compound and the additional agent may beadministered either simultaneously or sequentially. If administeredsequentially, the attending physician or caretaker can decide on theappropriate sequence of administering the compound and the additionaltherapeutic agent.

In some embodiments, a method comprising administering any of thecompounds described herein further comprises combination therapy with anadditional therapeutic regimen. The additional therapeutic regimen cancomprise implantation of a medical device. The medical device can beimplanted in the stomach and/or abdomen, e.g., in the duodenum. Themedical device can be an electrical device. The medical device can be apacemaker. Such a pacemaker can utilize electrical current to inducestomach and/or duodenal contractions, thereby promoting gastrointestinalmotility. Such medical devices, and methods of using them, are disclosedin U.S. Pat. No. 8,095,218, hereby incorporated by reference.

The invention is further described in detail by reference to thefollowing examples. These examples are provided for the purpose ofillustration only, and are not intended to be limiting unless otherwisespecified. Thus, the invention should in no way be construed as beinglimited to the following examples, but rather, should be construed toencompass any and all variations which become evident as a result of theteaching provided herein.

Example 1 Metopimazine and Metopimazine Acid are Selective and PotentDopamine D2 Receptor Antagonists

The pharmacological profile of metopimazine, metopimazine acid (MPZA),domperidone, and metoclopramide were assessed by radioligand binding andby a functional antagonist assay. For the radioligand binding assay,cell membranes of dopamine D2 receptor expressing cells were incubatedwith [3H]spiperone and competing drugs in buffer. The assay wasterminated by rapid filtration, and the bound radioactive signal wasdetermined by liquid scintillation counting. Results from the ligandbinding assay are depicted in Table 1, below.

TABLE 1 Pharmacological Profile. Radioligand Binding Affinity (Ki, nM)D2 D3 α1 5HT2 5HT3 5HT4 H1 Metopimazine (NG101) 0.07 0.61 1.90 15.0Inactive Inactive 8.40 Metopimazine-Acid (NG102) 14.0 >100 nM 210 370Inactive Inactive 140 Domperidone 1.30 7.50 Metoclopramide 64.0 16.0 

The functional antagonist assay was performed as described in Payne, S.L et al. (2002) J. Neurochem., 82: 1106-1117, hereby incorporated byreference. Specifically, [³⁵S]GTPγS binding assays were performed byincubating membranes from Dopaine D2 receptor expressing cells in abuffer supplemented with GDP and the drugs. After a definedpre-incubation period, [³⁵S]GTPγS was added to the reaction mixture. Theassay was incubated and then terminated as described in the radioligandbinding assay. Table 2 depicts results from the D2 functional antagonistassay.

TABLE 2 TABLE 2: Pharmacological profile: Dopamine D2 receptorantagonism. Compounds IC₅₀ (M) K_(B) (M) Metopimazine 2.2E−9 1.4E−10Metopimazine acid 3.1E−7 2.1E−8  Metoclopramide 2.8E−7 1.9E−8 Domperidone 3.4E−9 2.3E−10 Butaclamol (standard) 6.4E−9 4.2E−10

These studies demonstrated for the first time that metopimazine andmetopimazine-acid are potent and selective, D2 receptor antagonists.Furthermore, it was demonstrated that metopimazine and metopimazine acidact as peripherally restricted agents. Therapeutic plasma concentrationswere 50-200 nM for metopimazine and 300-900 nM for metopimazine-acid.

Example 2 Metopimazine and Metopimazine Acid do not Interact with hERGChannels

The ability of the compounds metopimazine, metopimazine acid, anddomperidone to inhibit hERG channels was assessed. Briefly,hERG—expressing cultured cells incubated in various concentrations ofthe drugs were subjected to a voltage clamp assay. Cells were held at a−70 mV resting membrane potential. hERG currents were elicited with asingle-pulse command voltage protocol using a depolarization to +40 mV.Elicited hERG currents were measured. Table 3, below, depictsexperimental results from the study.

TABLE 3 hERG Activity (% Inhibition of Tail Current) 100 nM 1 μM 10 μMMetopimazine 4.5 32 82 (NG101) Metopimazine- 0.2 4 11 Acid (NG102)Domperidone 55 92 100Results demonstrated that that the concentration necessary to inhibit50% of the tail currents mediated by hERG channels was approximately 3μM, >10 μM and 0.1 μM for metopimazine, metopimazine-acid anddomperidone respectively. Metopimazine and metopimazine-acid were foundto be 30 fold and >100 fold less potent, respectively, than domperidoneto inhibit hERG channels.

Example 3 Metopimazine and Carbidopa Promote Gastric Motility in Canines

The effects of metopimazine and carbidopa on gastric motility in vivowere assessed using antral manometry in canines Two healthy female hounddogs (24-28 kg) were involved in this study. Animals were fed an adlibitum chow diet (LabDiet®). After an overnight fast, the dogs wereanesthetized with Pentothal (sodium thiopental, 11 mg/kg IV; AbbottLaboratories, North Chicago, Ill.) and maintained on 2-4% isoflurane(Abbott Laboratories) in oxygen (1 L/min) carrier gases delivered from aventilator after endotracheal intubation. A cannula was placed in thejejunum 20 cm distal to the pylorus for the assessment of antralmotility. Dogs were allowed to recover in their individual cages for 2weeks. All experiments were performed after the dogs were completedrecovered from the surgical procedure. The study was performed accordingto the National Institutes of Health Guidelines on the use of laboratoryanimals and approved by the Animal Care and Use Committee of theUniversity of Texas Medical Branch at Galveston, Tex.

To investigate the effect of the drugs on antral manometry, the study ofeach drug dose was done on three randomized sessions on separate daysfollowing the consumption of one can of solid dog food: 1) a Controlsession: In which animals received the vehicle only; 2) Dose I session:in which the lower dose of the drug was used; and 3) Dose II session: inwhich the higher dose of the drug was used (please refer to table fordrug doses). Drug administration was performed according to Table 4,below.

TABLE 4 Drug administration protocol in canines Dose 1 Dose 2 Route ofDrug (mg/Kg) (mg/Kg) Vehicle administration Timing GM1 metopimazine 0.51 water Oral 15 min prior to meal GM2 S-Carbidopa 0.5 1 DMSO100 ml; thenadd IV 15 min water to attain volume prior to meal GM3 Dopamine 50mg/Dog 100 mg/Dog water IV Immediately hydrochloride before meal

Antral manometry was performed as follows. Following an overnight fast,an intraluminal water-perfused manometry catheter was inserted into theantrum through the jejunal cannula. Antral manometry recording wasinitiated after the consumption of one can of solid food and continuedfor 3 hours. The catheter contained 3 manometric sensors at a 1 cminterval. Dogs were given 10 minutes of accommodation, prior to thestart of the recording. For data analysis, motility index (MI), definedas the integrated area (area under curve—AUC) between baseline andcontractions per hour, was calculated.

For statistical analysis, the Student's t-test was used for assessmentof individual differences between groups (High dose, low dose of eachdrug) compared to control—Microsoft® Excel 2002). All values areexpressed as mean±SEM. Significance was considered when p value was≦0.05.

Results are shown in FIG. 2. Results demonstrate that the 1 mg/kg ofS-carbidopa robustly increased MI in all three of the channels tested(p=0.05). 1 mg/kg of metopimazine increased MI in all three channels ascompared to the control or lower dose (p=0.06). By contrast, dopaminehydrochloride (50 mg/canine) decreased MI in all channels (p=0.06).Furthermore, no motor dysfunction was observered in canines administeredmetopimazine or carbidopa. These results indicate that metopimazine andcarbidopa are both effective in enhancing gastric motility in vivo.

Example 4 Effect of Carbidopa on Gastric Emptying in Rodents

Animals:

Male Sprague-Dawley rats, purchased from the Charles River Lab, werehoused in the animal facility of Veterans Research Education Foundation,which was maintained at 22˜24° C., 55% relative humidity, with anautomatic 12 h light/dark cycle. The animals received a standardlaboratory rat chow and tap water ad libitum. The rats were around 400 gat 14 weeks age when used in gastric emptying study.

Drugs:

S-Carbidopa was purchased from Sigma (#: C1335). Stock solution ofS-Carbidopa was prepared at 5 mg/ml using DMSO as solvent. 80 μl stocksolution was further diluted into lml distilled water to make 0.4 mg/ml.The effect of S-Carbidopa (lmg/kg) on solid gastric emptying wasstudied.

Procedures:

Male SD rats were involved in this study. Rats were fasted in cages withmetal wired mesh for 24 hours with free access to water; S-carbidopa (1mg/kg) was administered to the rats by oral gavage. Control rats werenot administered S-carbidopa. 15 minutes following administration, ratswere given access to 2 g of rat chow pellets for ten minutes. All ratscompletely ingested the chow within the 10 minute time frame. Rats weresacrificed by sodium pentobarbital (100 mg/kg) overdose 90 min afterfeeding. The stomach was surgically isolated and removed. Gastriccontents were recovered from the stomach, air dried for 48 hours andthen weighed. Solid gastric emptying was calculated according to thefollowing formula: Gastric emptying (%)=[1−(dried gastric content ing)/2 g]×100. All values are expressed as mean±SEM. Significance wasconsidered when p value was <0.05.

Results:

Results from the rodent gastric emptying study are shown in Table 5below. In 8 normal rats not administered carbidopa, the gastric emptyingwas 57.4±4.7%. All of the rats depicted in Table 5 were administeredcarbidopa.

TABLE 5 Effect of S-Carbidopa (1 mg/kg) on solid gastric emptying Ratbody Food stomach Gastric ID Group weight given content emptying (%) 1 1mg/Kg 402 2 0.9 55 2 1 mg/Kg 400 2 0.76 62 3 1 mg/Kg 405 2 0.25 87.568.2

Initial results indicated that carbidopa improves solid gastric emptyingin rats compared to that in control rats that were not administeredcarbidopa. Furthermore, no motor dysfunction was observed in subjectsadministered carbidopa.

Example 5 Effect of Metopimazine on Gastric Emptying in Rodents

The effects of metopimazine (3 mg/kg and 10 mg/kg doses), metoclopramide(10 mg/kg), or vehicle administration on gastric emptying were assessedaccording to the protocol described in Example 4. Preliminary resultsare shown in FIG. 3, demonstrating that 3 mg/kg metopimazine increasedgastric emptying by about 18% as compared to vehicle control, and that10 mg/kg metopimazine increased gastric emptying by about 40% ascompared to vehicle control. The overall effect of metopimazine (bypooling the 3 mg/kg and 10 mg/kg doses) was an increase in gastricemptying of about 20% as compared to vehicle control. These resultsindicate for the first time that metopimazine increases gastric emptyingin vivo.

Example 6 Effect of Metopimazine, Metopimazine Acid on Cardiac ActionPotentials In Vivo

Effects of in vivo metopimazine, metopimazine acid, and carbidopa oncanine cardiac action potentials are assessed by electrocardiography andtelemetry.

Surgical Implantation of the Telemetry Device and ECG Leads.

Anesthesia is introduced to dogs. Balanced gaseous anesthesia is usedthroughout the surgical procedure. Once anesthetized, animals are shavedand surgically scrubbed, encompassing surgical sites of the rightinguinal area, chest and right lateral abdomen. Throughout the surgicalprocedure, animals are monitored for continuous assessment of vitalsigns. An incision is made along the right medial thigh and the femoralartery exposed by blunt dissection. Another incision is made in thelateral lumbar area cranial to the iliac crest for a tunneling needle tobe passed subcutaneously from the incision on the medial thigh to thelumbar incision. A blood pressure catheter is passed through the needlefrom the lumbar incision and the needle removed. The femoral artery isligated distally and incised to insert a catheter that is advanced untilthe tip resided in the femoral artery/abdominal aorta. The catheter isthen secured by ligation. The incision in the lumbar area is enlargedand a subcutaneous pocket created in the left dorsal lumbar area to holdthe transmitter body. The transmitter (e.g., Data SciencesInternational, St Paul, Minn., USA) is inserted into the subcutaneouspocket and secured body. Electrocardiography (ECG) leads are positioned.The incision is closed. Postoperative recovery lasts, e.g., about 2weeks during which supplemental analgesics/antibiotics are administeredas needed. Once the postoperative recovery period is complete, theanimal is examined for study acceptability by the staff veterinarian andthe implanted transmitter signal verified.

Study Design.

Subjects are administered vehicle, metopimazine, metopimazine acid,carbidopa, or 0.3 mg/kg dofetilide (as a positive control) by oralgavage. ECGs, heart rate and arterial blood pressure data are recorded 1hour prior to and then continuously for at least 6 hours followingcompound and/or vehicle administration. A blood sample for determinationof compound plasma concentrations is collected from all subjects atapproximately 6 h post-dose.

ECG Analysis.

An ECG waveform morphology assessment, for the entire monitoring period,is completed for each dog by, e.g., a safety pharmacologist orveterinarian cardiologist. Standard ECG intervals (PR, RR, QRS and QT)are automatically measured by the data acquisition system and reportedas, e.g., 10 min averages. The signals are collected with Data SciencesInternational Systems hardware. PR and QT manual overreads are conductedas appropriate. The manual measurements are completed from 50 mm s⁻¹tracings at 30 min intervals. A mean of the three waveforms per timepoint are reported. QT intervals are corrected for heart rate (QT_(c))values by, e.g., using the formula by Funck-Bretano and Jaillon (1993).

Statistical Analysis.

The systemic blood pressures and heart rate data radiotelemetry areaveraged across consecutive 10 min time intervals during the 6 hpost-dosing period for each animal. A baseline of a stable 10 min periodis selected prior to the start of dosing. The baseline measurement foreach animal is subtracted on each dosing day from the animal'spost-dosing 10 min averages. Dose-level averages (and accompanyingstandard deviation (s.d.) of these baseline-adjusted 10 min averages arecalculated across study animals. ANOVA (e.g., repeated measures ANOVA)are applied to these baseline-adjusted averages. Pairwise t-tests areapplied within the ANOVA to identify the presence of significantdifferences of the dose levels relative to vehicle. These t-tests areperformed at a 0.05/2=0.025 significance level, so that the overallerror rate across the comparisons in a given interval are not higherthan 0.05. ECG interval data (reported at 30 min intervals) are analyzedusing, e.g., repeated-measures ANOVA techniques similar to the systemicblood pressure and heart rate data described above.

QT_(c) intervals are increased in dogs administered dofetilidethroughout the post-dose period of 1-6 hours. Dofetilide administrationalso increases the incidence of premature ventricular contractions,T-wave abnormalities, and right bundle branch block. By contrast, nosignificant increases in QT_(c) intervals are found in dogs administeredmetopimazine, metopimazine acid, or carbidopa, as compared tovehicle-administered animals.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of treating an enteric nervous systemdisorder in a human subject in need thereof, comprising administering tothe subject an effective dose of a compound of formula III

or a pharmaceutically acceptable salt, solvate, or metabolite thereof,wherein the administering occurs for over 5 days.
 2. The method of claim1, wherein the administering occurs for over 7 days.
 3. The method ofclaim 1, wherein the administering occurs for over 12 weeks.
 4. Themethod of claim 1, wherein the administering occurs four times per day.5. The method of claim 1, wherein the effective dose is more than 30 mgof the compound a day.
 6. The method of claim 1, further comprisingco-administering to the human subject an additional therapeutic agent.7. The method of claim 6, wherein the additional therapeutic agent isselected from the group consisting of serotonin agonists, serotoninantagonists, selective serotonin reuptake inhibitors, anticonvulsants,opioid receptor agonists, bradykinin receptor antagonists, NK receptorantagonists, adrenergic receptor agonists, benzodiazepines,gonadotropin-releasing hormone analogues, calcium channel blockers, andsomatostatin analogs.
 8. The method of claim 6, wherein theco-administering comprises administering the additional therapeuticagent sequentially with the compound.
 9. The method of claim 6, whereinthe co-administering comprises administering the additional therapeuticagent simultaneously with the compound.
 10. The method of claim 1,further comprising co-administering to the human subject an effectivedose of a dopamine decarboxylase inhibitor.
 11. The method of claim 10,wherein the dopamine decarboxylase inhibitor does not cross ablood-brain barrier of the human subject.
 12. The method of claim 11,wherein the dopamine decarboxylase inhibitor is carbidopa.
 13. Themethod of claim 1, wherein the enteric nervous system disorder is achronic disorder.
 14. The method of claim 1, wherein the enteric nervoussystem disorder is selected from the group consisting of irritable bowelsyndrome, lysosomal storage disorders, intestinal dysmotility,ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B),gastrointestinal neuropathy, and intestinal neuronal dysplasia.
 15. Themethod of claim 1, wherein the enteric nervous system disorder isgastroparesis.
 16. The method of claim 1, wherein the enteric nervoussystem disorder causes a symptom which is selected from the groupconsisting of nausea, vomiting, delayed gastric emptying, diarrhea,abdominal pain, gas, bloating, gastroesophageal reflux, reducedappetite, and constipation.
 17. The method of claim 1, wherein theenteric nervous system disorder causes a symptom, wherein the symptom isassociated with Scleroderma, Parkinson's Disease, gastroesophagealreflux disease, Menetrier's Disease, a vestibular disorder,chemotherapy, cancer, drug use, or functional dyspepsia.
 18. The methodof claim 1, wherein the administering is oral, parenteral, enteral,intraperitoneal, topical, transdermal, ophthalmical, intranasal, local,via spray, subcutaneous, intravenous, intratonsillal, intramuscular,buccal, sublingual, rectal, intra-arterial, by infusion, or intrathecal.19. The method of claim 1, wherein the compound is in a pharmaceuticalcomposition comprising a physiologically acceptable vehicle.
 20. Themethod of claim 19, wherein the pharmaceutical composition is formulatedas a tablet, a capsule, a cream, a lotion, an oil, an ointment, a gel, apaste, a powder, a suspension, a syrup, an enema, an emulsion, asolution, or a controlled-release formulation.
 21. The method of claim19, wherein the pharmaceutical composition is an orally disintegratingtablet.
 22. The method of claim 1, wherein the administering does notincrease probability that the human subject will suffer an adversecardiac side effect.
 23. The method of claim 1, wherein theadministering does not increase probability that the human subject willsuffer an adverse extrapyramidal side effect.
 24. The method of claim 1,wherein the compound does not effectively cross a blood brain barrier.25. A kit, comprising: a) at least one unit dosage of a pharmaceuticalcomposition comprising a compound of Formula III:

and b) instructions for carrying out the method of claim
 1. 26. The kitof claim 25, further comprising a dopamine decarboxylase inhibitor. 27.The kit of claim 25, wherein the pharmaceutical composition does noteffectively cross a blood-brain barrier of a subject.
 28. The kit ofclaim 26, wherein the dopamine decarboxylase inhibitor is carbidopa. 29.The kit of claim 26, further comprising instructions for carrying outthe method of claim
 10. 30. A method of treating gastroparesis in ahuman subject in need thereof, comprising orally administering to thehuman subject a therapeutically effective amount of a compound offormula III

or a pharmaceutically acceptable salt, solvate, or metabolite thereoffor over 5 days.